COMT

Summary

COMT (catechol-O-methyltransferase, HGNC:2228) is a protein-coding gene on chromosome 22q11.21, encoding Catechol O-methyltransferase (P21964). Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones.

Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters.

Source: NCBI Gene 1312 — RefSeq curated summary.

At a glance

• Gene–disease (curated): paroxysmal dyskinesia (Moderate, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 157 total — 4 pathogenic
• GTEx eGene: eQTL in 37 tissues, sQTL in 41 (q < 0.05)
• Phenotypes (HPO): 131
• Drug target: yes — 4 curated mechanism-of-action drugs; 3 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 3 — Entacapone, Opicapone, Tolcapone
• Pharmacogenomics (PharmGKB): 3 CPIC/DPWG dosing guidelines (e.g. alfentanil;buprenorphine;codeine;fentanyl;hydrocodone;hydromorphone;levomethadone;morphine;naltrexone;remifentanil;sufentanil;tramadol, methadone;oxycodone, methylphenidate)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.13 (unconstrained)
• MANE Select transcript: NM_000754
• Interaction hub: 2,298 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2228
Approved symbol	COMT
Name	catechol-O-methyltransferase
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000093010
Ensembl biotype	protein_coding
OMIM	116790
Entrez	1312

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 28 protein_coding, 7 nonsense_mediated_decay, 5 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000361682

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 2, TSL 5: 3

ENST00000361682, ENST00000207636, ENST00000403184, ENST00000403710, ENST00000406520, ENST00000407537, ENST00000412786, ENST00000428707, ENST00000449653, ENST00000467943, ENST00000493893, ENST00000676678, ENST00000677397, ENST00000677470, ENST00000677564, ENST00000677675, ENST00000678240, ENST00000678255, ENST00000678769, ENST00000678868, ENST00000678945, ENST00000852828, ENST00000852829, ENST00000852830, ENST00000964893, ENST00000964894, ENST00000964895, ENST00000964896, ENST00000964897, ENST00000964898, ENST00000964899, ENST00000992256, ENST00001018379, ENST00001018381, ENST00001018382, ENST00001089268, ENST00001111104, ENST00001111105, ENST00001111106, ENST00001115038, ENST00001122591, ENST00001132000

RefSeq mRNA: 5 — MANE Select: NM_000754 NM_000754, NM_001135161, NM_001135162, NM_001362828, NM_007310

CCDS: CCDS13770, CCDS46663

Canonical transcript exons

ENST00000361682 — 6 exons

Exon	Start	End
ENSE00001056469	19961199	19961289
ENSE00001316383	19964168	19964299
ENSE00001656924	19962527	19962815
ENSE00001871649	19941772	19941897
ENSE00003569391	19963566	19963759
ENSE00004779850	19968536	19969975

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 78.9944 / max 544.4771, expressed in 1819 samples.

Highest expression (Bgee): adrenal gland cortex, adrenal gland, stromal cell of endometrium, olfactory bulb, adrenal cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

COMT is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 37 tissues and its splicing (sQTL) in 41 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 78 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	4.7e-100	+1.10	22:19962121:G:C
Muscle Skeletal	sqtl	2.7e-62	+0.84	22:19962121:G:C
Nerve Tibial	sqtl	4.1e-54	-0.84	22:19942028:A:G
Esophagus Mucosa	eqtl	1.9e-48	-0.40	22:19962121:G:C
Nerve Tibial	eqtl	1.4e-47	-0.72	22:19941996:G:A
Adipose Subcutaneous	eqtl	2.3e-38	-0.90	22:19937643:G:A
Adipose Subcutaneous	sqtl	1.5e-37	-0.62	22:19942028:A:G
Lung	sqtl	3.6e-37	-0.73	22:19942028:A:G
Cells EBV-transformed lymphocytes	eqtl	8.3e-36	+0.57	22:19942028:A:G
Skin Sun Exposed Lower leg	sqtl	3.5e-35	+0.66	22:19962429:A:G
Cells Cultured fibroblasts	eqtl	2.6e-34	-0.63	22:19943287:T:C
Esophagus Muscularis	eqtl	1.2e-32	-1.00	22:19943287:T:C
Artery Tibial	eqtl	7.0e-32	-0.66	22:19943287:T:C
Brain Cerebellar Hemisphere	sqtl	3.1e-30	-1.07	22:19960814:T:C
Brain Cerebellum	sqtl	3.7e-30	-1.03	22:19962121:G:C
Skin Not Sun Exposed Suprapubic	sqtl	2.4e-27	+0.66	22:19962121:G:C
Artery Tibial	sqtl	3.1e-26	+0.59	22:19962429:A:G
Heart Atrial Appendage	sqtl	2.6e-25	+0.83	22:19962121:G:C
Cells EBV-transformed lymphocytes	sqtl	2.9e-23	+0.84	22:19962121:G:C
Artery Aorta	eqtl	3.1e-23	-0.86	22:19937643:G:A

FANTOM5 promoters

showing 10 of 14 alternative TSS:

Promoter ID	TPM avg	Samples expressed
191081	40.5983	1722
191084	11.8871	1668
191090	10.7661	830
191082	9.0914	1695
191091	2.5021	456
191083	1.7310	1158
191097	0.6662	390
191093	0.5784	345
191096	0.3538	166
191089	0.3131	172

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	98.95	gold quality
right adrenal gland	UBERON:0001233	98.92	gold quality
stromal cell of endometrium	CL:0002255	98.90	gold quality
left adrenal gland	UBERON:0001234	98.83	gold quality
olfactory bulb	UBERON:0002264	98.82	gold quality
left adrenal gland cortex	UBERON:0035825	98.82	gold quality
adrenal cortex	UBERON:0001235	98.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.76	gold quality
spinal cord	UBERON:0002240	98.54	gold quality
pharyngeal mucosa	UBERON:0000355	98.43	gold quality
right lobe of liver	UBERON:0001114	98.40	gold quality
corpus callosum	UBERON:0002336	98.23	gold quality
esophagus mucosa	UBERON:0002469	98.14	gold quality
renal medulla	UBERON:0000362	98.10	gold quality
adrenal gland	UBERON:0002369	98.10	gold quality
left ovary	UBERON:0002119	98.07	gold quality
right ovary	UBERON:0002118	98.02	gold quality
right lung	UBERON:0002167	97.99	gold quality
body of tongue	UBERON:0011876	97.98	gold quality
nerve	UBERON:0001021	97.96	gold quality
tibial nerve	UBERON:0001323	97.96	gold quality
amygdala	UBERON:0001876	97.88	gold quality
ascending aorta	UBERON:0001496	97.87	gold quality
thoracic aorta	UBERON:0001515	97.87	gold quality
right coronary artery	UBERON:0001625	97.82	gold quality
tongue	UBERON:0001723	97.82	gold quality
ectocervix	UBERON:0012249	97.82	gold quality
endocervix	UBERON:0000458	97.78	gold quality
decidua	UBERON:0002450	97.78	gold quality
saliva-secreting gland	UBERON:0001044	97.72	gold quality
body of stomach	UBERON:0001161	97.72	gold quality
superior surface of tongue	UBERON:0007371	97.68	gold quality
trigeminal ganglion	UBERON:0001675	97.66	gold quality
minor salivary gland	UBERON:0001830	97.66	gold quality
skin of abdomen	UBERON:0001416	97.65	gold quality
nipple	UBERON:0002030	97.61	gold quality
putamen	UBERON:0001874	97.57	gold quality
upper lobe of left lung	UBERON:0008952	97.57	gold quality
left coronary artery	UBERON:0001626	97.53	gold quality
mouth mucosa	UBERON:0003729	97.50	gold quality
upper lobe of lung	UBERON:0008948	97.50	gold quality
nucleus accumbens	UBERON:0001882	97.49	gold quality
hypothalamus	UBERON:0001898	97.45	gold quality
fundus of stomach	UBERON:0001160	97.44	gold quality
monocyte	CL:0000576	97.43	gold quality
coronary artery	UBERON:0001621	97.43	gold quality
descending thoracic aorta	UBERON:0002345	97.42	gold quality
esophagus	UBERON:0001043	97.41	gold quality
corpus epididymis	UBERON:0004359	97.40	gold quality
parotid gland	UBERON:0001831	97.39	gold quality
liver	UBERON:0002107	97.37	gold quality
saphenous vein	UBERON:0007318	97.37	gold quality
skin of leg	UBERON:0001511	97.34	gold quality
aorta	UBERON:0000947	97.33	gold quality
pericardium	UBERON:0002407	97.33	gold quality
mucosa of stomach	UBERON:0001199	97.26	gold quality
endometrium epithelium	UBERON:0004811	97.24	gold quality
inferior vagus X ganglion	UBERON:0005363	97.23	gold quality
mononuclear cell	CL:0000842	97.22	gold quality
lower esophagus mucosa	UBERON:0035834	97.17	gold quality
caudate nucleus	UBERON:0001873	97.13	gold quality
leukocyte	CL:0000738	97.11	gold quality
gall bladder	UBERON:0002110	97.11	gold quality
trachea	UBERON:0003126	97.10	gold quality
superior vestibular nucleus	UBERON:0007227	97.09	gold quality
medulla oblongata	UBERON:0001896	97.04	gold quality
body of uterus	UBERON:0009853	97.00	gold quality
left uterine tube	UBERON:0001303	96.99	gold quality
peritoneum	UBERON:0002358	96.99	gold quality
omental fat pad	UBERON:0010414	96.99	gold quality
popliteal artery	UBERON:0002250	96.96	gold quality
tibial artery	UBERON:0007610	96.95	gold quality
right frontal lobe	UBERON:0002810	96.93	gold quality
zone of skin	UBERON:0000014	96.92	gold quality
vena cava	UBERON:0004087	96.91	gold quality
cardia of stomach	UBERON:0001162	96.88	gold quality
ventricular zone	UBERON:0003053	96.88	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.88	gold quality
metanephros cortex	UBERON:0010533	96.83	gold quality
pylorus	UBERON:0001166	96.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.80	gold quality
gluteal muscle	UBERON:0002000	96.78	gold quality
lower esophagus	UBERON:0013473	96.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.70	gold quality
placenta	UBERON:0001987	96.65	gold quality
right atrium auricular region	UBERON:0006631	96.64	gold quality
stomach	UBERON:0000945	96.60	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.59	gold quality
ventral tegmental area	UBERON:0002691	96.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.51	gold quality
apex of heart	UBERON:0002098	96.46	gold quality
vagina	UBERON:0000996	96.41	gold quality
gastrocnemius	UBERON:0001388	96.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.35	gold quality
dorsal root ganglion	UBERON:0000044	96.31	gold quality
subthalamic nucleus	UBERON:0001906	96.31	gold quality
cingulate cortex	UBERON:0003027	96.29	gold quality
lower lobe of lung	UBERON:0008949	96.29	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	128.19
E-HCAD-4	yes	68.70
E-HCAD-11	yes	33.10
E-HCAD-10	yes	22.73
E-MTAB-8410	yes	20.37
E-HCAD-13	yes	11.58
E-MTAB-10042	yes	9.25
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spinal cord	tissue	168.1
Choroid plexus	tissue	141.7
Medulla oblongata	tissue	139.5
Thalamus	tissue	131.6
Superior colliculi	tissue	131.2
Liver	tissue	131.2	low
Midbrain	tissue	129.2
Substantia nigra	tissue	126.0
Salivary gland	tissue	125.9	medium
Pons	tissue	125.5
Cerebral cortex	tissue	123.5	medium
Somatosensory cortex	tissue	123.5
Motor cortex	tissue	120.2
Occipital cortex	tissue	115.8
Vagina	tissue	115.7	not detected
Periaqueductal gray	tissue	113.4
Caudate putamen	tissue	113.4
Placenta	tissue	109.9	high
Prefrontal cortex	tissue	109.6
Adrenal gland	tissue	108.4	medium
Hippocampal formation	tissue	107.8
Entorhinal cortex	tissue	107.8
Temporal cortex	tissue	106.4
Frontal cortex	tissue	106.0
Putamen	tissue	106.0
Esophagus	tissue	105.3	medium
Hypothalamus	tissue	105.2
Insular cortex	tissue	99.8
Retrosplenial cortex	tissue	97.5
Retrosplenial and cingulate cortex	tissue	96.4
Ventral forebrain	tissue	96.2
Basal ganglia	tissue	94.5	medium
Corpus callosum	tissue	94.4
Hippocampus	tissue	92.8	low
Septum	tissue	90.1
Amygdala	tissue	86.7
Nucleus accumbens	tissue	81.2
Locus coeruleus	tissue	79.7
Ovary	tissue	78.5	medium
Lung	tissue	75.6	medium
Heart muscle	tissue	71.9	not detected
Olfactory bulb	tissue	71.6
Urinary bladder	tissue	69.2	high
Pancreas	tissue	67.7	medium
Bone marrow	tissue	67.7	medium
Skin 1	tissue	67.2	high
Seminal vesicle	tissue	66.5	medium
Breast	tissue	62.1	medium
Stomach 1	tissue	60.3	medium
Prostate	tissue	58.2	medium
Postcentral gyrus	tissue	58.1
Parathyroid gland	tissue	57.8	medium
Cerebellum	tissue	57.6	high
Gallbladder	tissue	56.6	medium
Small intestine	tissue	55.4	medium
Skeletal muscle	tissue	54.5	not detected
Duodenum	tissue	51.7	medium
Cervix	tissue	50.3	medium
Lymph node	tissue	46.6	low
Tongue	tissue	46.6

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (168.1), Dorsal funiculus (white matter) (148.6), Nucleus raphe pallidus (140.7), Parieto-temporal junction (white matter) (136.9), Corpus callosum, genu (white matter) (136.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, ESR1, IKBKB, INS, KAT7, NFKB, PGR, RELA, TNF

miRNA regulators (miRDB)

Targeting COMT by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 52 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628

Functional genomics

gnomAD constraint: pLI 0.000498, LOEUF 1.13, missense Z 0.74 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000361682 — one region, missense o/e 0.91.

Literature-anchored findings (GeneRIF, showing 40)

• A low-activity allele is associated with obsessive-compulsive bahavior in females, not in males as previously reported. (PMID:11840516)
• COMT activity may determine the individual response to levodopa and result in ethnic differences in Parkinson disease susceptibility. (PMID:11873938)
• possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol-O-methyltransferase (COMT) G158A, monoamine oxydase A (MAO-A) 30-bp repeat, G-protein beta 3-subunit (Gbeta3) C825T (PMID:11992559)
• possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders (PMID:11992560)
• Association between catechol-O-methyltransferase polymorphism and vitiligo. (PMID:12029502)
• polymorphism associated with schizophrenia in Chinese families in China (PMID:12082558)
• allelic variants of COMT gene may modulate the risk for schizophrenia (PMID:12090821)
• that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. (PMID:12192614)
• Characterization of human soluble high and low activity allele-catalyzed catechol estrogen methylation. (PMID:12360102)
• A highly significant association between a COMT haplotype and schizophrenia (PMID:12402217)
• catalyzes the o-methylation inactivation pathway of the major metabolites of estrogen, 2- hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2). (PMID:12402217)
• Results suggested that liability to heroin-dependence was associated with -287 A/G polymorphism of COMT gene. (PMID:12476424)
• Contrary to expectations that COMT would be expressed predominantly in non-neuronal cells, the present study shows that neurons are the main cell populations expressing COMT mRNA in the prefrontal cortex and striatum. (PMID:12535946)
• Serum estradiol levels significantly correlate with COMT genotype. Differences in COMT genotype might be involved in causing variable effects of estrogens on diseases and on efficacy of hormone replacement therapy. (PMID:12571159)
• individuals homozygous for the met158 allele of the catechol-O-methyltransferase polymorphism (val158met) showed diminished regional mu-opioid system responses to pain compared with heterozygotes (PMID:12595695)
• There is an inherited difference in COMT polymorphism which is important in the pathogenesis of anxiety in women. (PMID:12605099)
• examination of gene polymorphism in postmenopausal cancer risk (PMID:12727796)
• the risk of having both low activity catechol-O-methyltransferase and high angiotensin-converting enzyme genotypes was over 10 times higher in schizophrenics with poor response to conventional neuroleptics (PMID:12729939)
• COMT polymorphism is of potential pharmacological importance to individual differences in the metabolism of catechol drugs and may be involved in the pathogenesis and treatment of fibromyalgia syndrome. (PMID:12739038)
• val/met variants in novelty seeking behavior (PMID:12740593)
• This study does not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders. (PMID:12782971)
• Disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the dorsolateral prefrontal cortex of patients with schizophrenia. (PMID:12799619)
• Methylation of multiple promoters of the COMT gene can selectively inactivate MB-COMT and may contribute to endometrial carcinogenesis. (PMID:12810635)
• Low COMT activity is associated with aggressive behavior in schizophrenia. (PMID:12815735)
• No significant association was found in Japanese patients between COMT polymorphism and schizophrenia. (PMID:12815736)
• There is an association between Val108/158 Met polymorphism of the COMT gene in schizophrenia. (PMID:12815739)
• There was a weak association with COMT genotype in neuroticism when the males and females were considered separately. There was no significant interaction between COMT and MAOA. (PMID:12815746)
• The functional polymorphism in the COMT gene may modify the phenotype of suicide attempts and anger-related traits. (PMID:12842306)
• The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this single nucleotide polymorphism. (PMID:12842307)
• COMT gene polymorphism is not directly associated with obsessive-compulsive disorder (PMID:12900951)
• Data suggested that for the Han Chinese children with ADHD in the study, there was no association between ADHD and Val158Met polymorphism of COMT gene. (PMID:12903043)
• These findings indicate that COMT genotype is associated with several risk factors for breast cancer and suggest that the low-activity COMT*2 allele is associated with a reduced risk of breast cancer among premenopausal women. (PMID:14504192)
• COMT gene polymorphism significantly increased the risk of developing prostate carcinoma. (PMID:14508827)
• Catechol-O-methyltransferase (COMT( deficiency in mice increases the availability of L-DOPA, leading to enhanced dopaminergic tone, which may be associated with resistance to salt-induced hypertension. (PMID:14654758)
• Compared with the COMT Val/Val wildtype genotype, the adjusted odds ratio of endometrial cancer for women with the COMT Val/ (PMID:14656940)
• The catechol O-methyltransferase gene has been associated with cognitive and behavioral phenotypes in schizophrenia (PMID:14754787)
• The Met108 allozyme displayed a 70-90% decrease in immunoreactive protein when compared with WT, but there was no significant change in the level of immunoreactive protein for Thr52 (PMID:14966473)
• The Catechol-o-methyltransferase gene polymorphism is not associated with the generation and the severity of pregnancy induced hypertension. (PMID:14989982)
• There were no observed differences in the frequencies of allele and genotype between obsessive-compulsive disorder patients and control groups for COMT polymorphisms. (PMID:15005715)
• a role of the catechol-O-methyltransferase gene polymorphism in the pathogenesis of panic disorder in women (PMID:15009906)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	comta	ENSDARG00000015337
danio_rerio	comtb	ENSDARG00000025679
mus_musculus	Comt	ENSMUSG00000000326
rattus_norvegicus	Comt	ENSRNOG00000001889
caenorhabditis_elegans		WBGENE00012518
caenorhabditis_elegans		WBGENE00021487
caenorhabditis_elegans		WBGENE00021491
caenorhabditis_elegans		WBGENE00021492

Paralogs (2): COMTD1 (ENSG00000165644), TOMT (ENSG00000284844)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88470) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 39 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased dopamine level	2
abnormal behavior	2
abnormal impulsive behavior control	2
hypertension	1
increased aggression towards male mice	1
increased anxiety-related response	1
decreased anxiety-related response	1
abnormal locomotor behavior	1
hyperactivity	1
abnormal temporal memory	1
increased circulating phosphate level	1
abnormal placenta morphology	1
abnormal homeostasis	1
abnormal associative learning	1
abnormal fertility/fecundity	1
short gestation period	1
albuminuria	1
decreased hemoglobin content	1
decreased erythrocyte cell number	1
increased circulating alanine transaminase level	1
abnormal placenta vasculature	1
abnormal response to novel object	1
abnormal spongiotrophoblast layer morphology	1
abnormal maternal decidual layer morphology	1
hypoxia	1

+14 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	P86243	99.3%	Diamond
Macaca mulatta	B6CZ46	95.6%	Diamond
Propithecus coquereli	B6CZ56	92.6%	Diamond
Equus caballus	Q5H879	87.2%	Diamond
Sus scrofa	Q99028	87.2%	Diamond
Bos taurus	A7MBI7	83.9%	Diamond
Schizosaccharomyces pombe 972h-	O42898	52.0%	Diamond
Niastella koreensis GR20-10	G8T6H8	49.8%	Diamond
Mycobacterium tuberculosis H37Rv	O07431	49.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR4761	ncRNA	100616414
TXNRD2	protein-coding	10587
GNB1L	protein-coding	54584
RTL10	protein-coding	79680
TANGO2	protein-coding	128989
MIR185	ncRNA	406961
ARVCF	protein-coding	421
MIR3618	ncRNA	100500860
DGCR8	protein-coding	54487
MIR1306	ncRNA	100302197

Protein

Protein identifiers

Catechol O-methyltransferase — P21964 (reviewed: P21964)

All UniProt accessions (8): A0A140VJG8, A0A7I2V370, A0A7I2V3G7, E7EMS6, E7EUU8, P21964, F8WBW9, H7BZ45

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.

Subcellular location. Cytoplasm Cell membrane.

Tissue specificity. Brain, liver, placenta, lymphocytes and erythrocytes.

Post-translational modifications. The N-terminus is blocked.

Disease relevance. Schizophrenia (SCZD) [MIM:181500] A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Polymorphism. Two major alleles, COMT1 or COMTH and COMT2 or COMTL are defined by a nucleotide G-to-A transition at codon 158, resulting in a valine-to-methionine substitution. Allele COMT*2 codes for protein variant p.Val158Met, a functional polymorphism resulting in 3- to 4-fold difference in catechol O-methyltransferase activity [MIM:621296]. Low enzyme activity alleles are associated with genetic susceptibility to alcoholism [MIM:103780].

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P21964-1	Membrane-bound, MB-COMT	yes
P21964-2	Soluble, S-COMT

RefSeq proteins (5): NP_000745, NP_001128633, NP_001128634, NP_001349757, NP_009294 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002935	SAM_O-MeTrfase	Family
IPR017128	Catechol_O-MeTrfase_euk	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF01596

Enzyme classification (BRENDA)

• EC 2.1.1.6 — catechol O-methyltransferase (BRENDA: 26 organisms, 218 substrates, 355 inhibitors, 169 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

36 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DOPAMINE	0.0005–48.071	31
S-ADENOSYL-L-METHIONINE	0.0031–3.9	24
NOREPINEPHRINE	0.0055–1.856	19
2-HYDROXYESTRADIOL	0.0001–0.0175	11
ADRENALINE	0.0014–0.48	9
CATECHOL	0.0084–0.833	7
EPINEPHRINE	0.009–0.3947	7
4-HYDROXYESTRADIOL	0.0004–0.0161	5
SALVIANOLIC ACID B	0.0113–0.0797	4
EPIGALLOCATECHIN GALLATE	0.0002–0.0048	3
ESCULETIN	0.0004–0.015	3
QUERCETIN	0.0015–0.0069	3
CATECHIN	0.0022–0.0089	2
EPICATECHIN	0.0043–0.0257	2
EPIGALLOCATECHIN	0.0081–0.0117	2

Catalyzed reactions (Rhea)

• a catechol + S-adenosyl-L-methionine = a guaiacol + S-adenosyl-L-homocysteine + H(+) (RHEA:17877)
• 2-hydroxy-17beta-estradiol + S-adenosyl-L-methionine = 2-methoxy-17beta-estradiol + S-adenosyl-L-homocysteine + H(+) (RHEA:53088)
• 2-hydroxy-17beta-estradiol + S-adenosyl-L-methionine = 2-hydroxy-3-methoxy-17beta-estradiol + S-adenosyl-L-homocysteine + H(+) (RHEA:53092)
• 4-hydroxy-17beta-estradiol + S-adenosyl-L-methionine = 4-methoxy-17beta-estradiol + S-adenosyl-L-homocysteine + H(+) (RHEA:53096)
• 2-hydroxyestrone + S-adenosyl-L-methionine = 2-methoxyestrone + S-adenosyl-L-homocysteine + H(+) (RHEA:53100)
• 4-hydroxyestrone + S-adenosyl-L-methionine = 4-methoxyestrone + S-adenosyl-L-homocysteine + H(+) (RHEA:53104)
• 2-hydroxyestrone + S-adenosyl-L-methionine = 2-hydroxy-3-methoxy-estrone + S-adenosyl-L-homocysteine + H(+) (RHEA:53108)

UniProt features (47 total): binding site 14, helix 13, strand 8, sequence variant 5, topological domain 2, chain 1, modified residue 1, splice variant 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures by resolution:

PDB	Title	Method	Resolution (Å)
3BWY	Crystal Structure of Human 108M Catechol O-methyltransferase bound with …	X-RAY DIFFRACTION	1.3
6I3C	Crystal structure of Human soluble catechol O-methyltransferase in complex with …	X-RAY DIFFRACTION	1.34
4PYI	human apo COMT	X-RAY DIFFRACTION	1.35
6I3D	Crystal structure of Human soluble catechol O-methyltransferase in complex with …	X-RAY DIFFRACTION	1.45
5LSA	human catechol O-methyltransferase in complex with SAM and DNC at 1.50A	X-RAY DIFFRACTION	1.5
4XUC	Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of …	X-RAY DIFFRACTION	1.8
4PYJ	human apo-COMT, single domain swap	X-RAY DIFFRACTION	1.9
3BWM	Crystal Structure of Human Catechol O-Methyltransferase with bound SAM and DNC	X-RAY DIFFRACTION	1.98
4PYK	human COMT, double domain swap	X-RAY DIFFRACTION	2.22
4XUE	Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of …	X-RAY DIFFRACTION	2.3
4XUD	Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of …	X-RAY DIFFRACTION	2.4
3A7E	Crystal structure of human COMT complexed with SAM and 3,5-dinitrocatechol	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21964-F1	94.07	0.81

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Mental and behavioural disorders

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles; endoplasmic reticulum

Antibody reliability (HPA): IH enhanced · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (14)

Position	Role
169	S-adenosyl-L-methionine
191	Mg(2+)
191	S-adenosyl-L-methionine
194	substrate
219	Mg(2+)
220	Mg(2+)
220	substrate
249	substrate
92	S-adenosyl-L-methionine
114	S-adenosyl-L-methionine
122	S-adenosyl-L-methionine
140	S-adenosyl-L-methionine
141	S-adenosyl-L-methionine
167–170	S-adenosyl-L-methionine

Post-translational modifications (1)

Type	Positions
Phosphoserine	267

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 15; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-9679191	Potential therapeutics for SARS ⚕	curated
R-HSA-379398	Enzymatic degradation of Dopamine by monoamine oxidase	curated
R-HSA-379397	Enzymatic degradation of dopamine by COMT	curated
R-HSA-156581	Methylation	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-211859	Biological oxidations	—
R-HSA-379401	Dopamine clearance from the synaptic cleft	—
R-HSA-1430728	Metabolism	—
R-HSA-112316	Neuronal System	—
R-HSA-112311	Neurotransmitter clearance	—
R-HSA-156580	Phase II - Conjugation of compounds	—
R-HSA-112315	Transmission across Chemical Synapses	—

MSigDB gene sets: 681 (showing top): GOBP_MEMORY, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_93, GOBP_EXCRETION, GOBP_DIGESTION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_COGNITION, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE

GO Biological Process (7): lipid metabolic process (GO:0006629), methylation (GO:0032259), developmental process (GO:0032502), dopamine metabolic process (GO:0042417), dopamine catabolic process (GO:0042420), catecholamine catabolic process (GO:0042424), catecholamine metabolic process (GO:0006584)

GO Molecular Function (7): magnesium ion binding (GO:0000287), methyltransferase activity (GO:0008168), O-methyltransferase activity (GO:0008171), catechol O-methyltransferase activity (GO:0016206), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), postsynaptic density (GO:0014069), vesicle (GO:0031982)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Dopamine clearance from the synaptic cleft	2
Phase II - Conjugation of compounds	1
SARS-CoV Infections	1
Transmission across Chemical Synapses	1
Neuronal System	1
Biological oxidations	1
Metabolism	1
Neurotransmitter clearance	1
Disease	1
Viral Infection Pathways	1
Infectious disease	1

GO top-level categories

31 GO namespaces:

Category	Terms
cellular anatomical structure	3
catecholamine metabolic process	2
cytoplasm	2
neuron projection	2
primary metabolic process	1
metabolic process	1
biological_process	1
dopamine metabolic process	1
catecholamine catabolic process	1
catechol-containing compound catabolic process	1
biogenic amine catabolic process	1
biogenic amine metabolic process	1
catechol-containing compound metabolic process	1
metal ion binding	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
O-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
binding	1
catalytic activity	1
cation binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
dendritic tree	1
extracellular vesicle	1
intracellular anatomical structure	1
asymmetric synapse	1
postsynaptic specialization	1
membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
catecholamine catabolic process	BP	direct assay
methylation	BP	direct assay
cytosol	CC	direct assay
endoplasmic reticulum	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
catechol O-methyltransferase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,298 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMT	SLC6A4	P31645	944
COMT	DRD4	P21917	942
COMT	MAOA	P21397	937
COMT	MAOB	P27338	937
COMT	DRD2	P14416	929
COMT	SLC6A3	Q01959	923
COMT	ARVCF	O00192	886
COMT	HTR2A	P28223	855
COMT	ANKK1	Q8NFD2	849
COMT	BDNF	P23560	825
COMT	DBH	P09172	806
COMT	DDC	P20711	801
COMT	PRODH	O43272	793
COMT	PRODH	O43272	779
COMT	TPMT	P51580	776

IntAct

Human interaction partners of COMT in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 74 partners by confidence:

Partner	Interaction type	MIscore	Records
SLC7A1	physical association	0.670	3
TMEM205	physical association	0.670	3
TRIP13	physical association	0.620	3
AQP7	physical association	0.560	3
AVPR2	physical association	0.560	3
BEST2	physical association	0.560	3
CCL4L1	physical association	0.560	3
CNR2	physical association	0.560	3
CREB3L1	physical association	0.560	3
EMD	physical association	0.560	3
FAM209A	physical association	0.560	3
FFAR3	physical association	0.560	3
GET1	physical association	0.560	3
GJB1	physical association	0.560	3
GJB3	physical association	0.560	3
GJB4	physical association	0.560	3
GJB5	physical association	0.560	3
GPR152	physical association	0.560	3
GPR161	physical association	0.560	3
GPR42	physical association	0.560	3
HIBADH	physical association	0.560	3
HSD3B7	physical association	0.560	3
KCNK5	physical association	0.560	3
MFSD14B	physical association	0.560	3
MYADML2	physical association	0.560	3
NIPAL4	physical association	0.560	3
OTOP3	physical association	0.560	3
PGAP2	physical association	0.560	3
PLPP6	physical association	0.560	3
REEP4	physical association	0.560	3

BioGRID (217 interactions; top human partners by supporting records): TRIP13 (Two-hybrid; 3 records), CDC42 (Co-fractionation; 2 records), RUFY1 (Affinity Capture-MS; 2 records), SLC7A1 (Two-hybrid; 2 records), TMEM205 (Two-hybrid; 2 records), ABHD11 (Co-fractionation), ANLN (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1G1 (Affinity Capture-MS), AP1G2 (Affinity Capture-MS), AP1M1 (Affinity Capture-MS), AP1S1 (Affinity Capture-MS), AP1S2 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS)

SIGNOR signaling

showing 10 of 12 signaling interactions:

A	Effect	B	Mechanism
INS	“up-regulates quantity by expression”	COMT	“transcriptional regulation”
17beta-hydroxy-5alpha-androstan-3-one	up-regulates	COMT
RELA	“down-regulates quantity by repression”	COMT	“transcriptional regulation”
IKBKB	“down-regulates quantity by repression”	COMT	“transcriptional regulation”
entacapone	“down-regulates activity”	COMT	“chemical inhibition”
tolcapone	“down-regulates activity”	COMT	“chemical inhibition”
COMT	“down-regulates quantity”	dopamine	“chemical modification”
COMT	“up-regulates quantity”	3-methoxytyramine	“chemical modification”
TNF	“down-regulates quantity by repression”	COMT	“transcriptional regulation”
progesterone	down-regulates	COMT

Disease & clinical

Genetic variants

Variant evidence for COMT: 157 ClinVar records (4 pathogenic / likely pathogenic); 3 PharmGKB dosing guidelines; 7 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

157 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	37
Likely benign	23
Benign	14

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2500149	NM_000754.4(COMT):c.575_576insT (p.Trp193fs)	Pathogenic	criteria provided, single submitter	1
1808679	GRCh37/hg19 22q11.21(chr22:19336598-21208828)x1	Pathogenic	criteria provided, single submitter	1
2684929	GRCh37/hg19 22q11.21(chr22:19533622-19938011)x3	Pathogenic	criteria provided, single submitter	1
2574689	GRCh37/hg19 22q11.21(chr22:18916842-20311810)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore COMT’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 1,064):

Position(s)	Effect	Δscore	Sites
22:19962816–19962817	donor_loss	1.0000	5
22:19963555–19963556	acceptor_gain	1.0000	2
22:19963559	acceptor_gain	1.0000
22:19963563	acceptor_gain	1.0000
22:19963564–19963565	acceptor_loss	1.0000	5
22:19963760–19963761	donor_loss	1.0000	4
22:19964166–19964167	acceptor_loss	1.0000	3
22:19941898–19941899	donor_loss	0.9900	5
22:19962799	donor_gain	0.9900
22:19963761	donor_loss	0.9900

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:116790 | disease phenotypes: MIM:209900

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
paroxysmal dyskinesia	Moderate	Autosomal dominant

Mondo (2): Bardet-Biedl syndrome (MONDO:0015229), paroxysmal dyskinesia (MONDO:0015427)

Orphanet (1): Bardet-Biedl syndrome (Orphanet:110)

HPO phenotypes

showing 60 of 131 phenotypes (HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000130	Abnormality of the uterus
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000389	Chronic otitis media
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000492	Abnormal eyelid morphology
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000582	Upslanted palpebral fissure
HP:0000600	Abnormality of the pharynx
HP:0000627	Posterior embryotoxon
HP:0000648	Optic atrophy
HP:0000670	Carious teeth
HP:0000682	Abnormal dental enamel morphology
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000717	Autism
HP:0000739	Anxiety
HP:0000765	Abnormal thorax morphology
HP:0000778	Hypoplasia of the thymus
HP:0000821	Hypothyroidism
HP:0000829	Hypoparathyroidism
HP:0000836	Hyperthyroidism
HP:0000929	Abnormal skull morphology
HP:0000979	Purpura
HP:0001051	Seborrheic dermatitis
HP:0001053	Hypopigmented skin patches
HP:0001061	Acne
HP:0001081	Cholelithiasis

GWAS associations

7 associations:

Study	Trait	p-value
GCST009733_172	Urinary metabolite levels in chronic kidney disease	2e-59
GCST009735_45	Urinary metabolite modules (eigenmetabolites) in chronic kidney disease	5e-54
GCST006249_98	Serum metabolite levels	1e-48
GCST009733_220	Urinary metabolite levels in chronic kidney disease	2e-28
GCST009733_219	Urinary metabolite levels in chronic kidney disease	2e-11
GCST006249_82	Serum metabolite levels	6e-11
GCST006434_6	Systolic blood pressure x alcohol consumption interaction (2df test)	3e-8

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2023 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the COMT protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

4 curated-mechanism drugs:

Drug	Modality	Max phase
ENTACAPONE	Small molecule	4
OPICAPONE	Small molecule	4
TOLCAPONE	Small molecule	4
NEBICAPONE	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 31,573 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL953	ENTACAPONE	4	16,953
CHEMBL1089318	OPICAPONE	4	685
CHEMBL1324	TOLCAPONE	4	13,935

PharmGKB: 1 entry (CPIC guideline: yes)

PharmGKB clinical annotations

showing 56 of 68 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs13306278	Efficacy	3	Selective serotonin reuptake inhibitors	Major Depressive Disorder
rs165599	Efficacy	3	risperidone	Schizophrenia
rs165599	Efficacy	3	bupropion	Tobacco Use Disorder
rs4633	Other	3	opioids	Pain
rs4633	Toxicity	3	opioids	Dizziness
rs4633	Toxicity	3	opioids	Physiological sexual disorder
rs4633	Efficacy	3	butorphanol
rs4646316	Toxicity	3	cisplatin	Drug Toxicity;Neoplasms;Ototoxicity
rs4646316	Toxicity	3	cisplatin	Neoplasms;Nephrotoxicity
rs4680	Toxicity	3	antipsychotics	Tardive Dyskinesia
rs4680	Other	3	opioids	Pain
rs4680	Efficacy	3	venlafaxine	Anxiety Disorders;Depressive Disorder
rs4680	Other	3	Analgesics;Antiinflammatory agents;non-steroids;Ergot alkaloids;opioids;sumatriptan
rs4680	Toxicity	3	nicotine	Tobacco Use Disorder
rs4680	Efficacy	3	modafinil	Methamphetamine dependence
rs4680	Toxicity	3	opioids	Hyperalgesia
rs4680	Toxicity	3	opioids	Death;Opioid-Related Disorders
rs4680	Toxicity	3	methadone	Neonatal Abstinence Syndrome
rs4680	Efficacy	3	nicotine	Tobacco Use Disorder
rs4680	Other	3	antipsychotics	Schizophrenia
rs4680	Toxicity	3	buprenorphine;fentanyl;tramadol	Exanthema;Opioid-Related Disorders
rs4680	Toxicity	3	buprenorphine	Neonatal Abstinence Syndrome
rs4680	Efficacy	3	fentanyl	Pain
rs4680	Toxicity	3	fentanyl	Somnolence
rs4680	Dosage	3	morphine	Pain;Pain;Postoperative
rs4680	Efficacy	3	remifentanil	Pain
rs4680	Efficacy	3	opioids	Pain
rs4680	Efficacy	3	oxycodone
rs4680	Efficacy	3	fluvoxamine	Major Depressive Disorder
rs4680	Dosage	3	opioids	Pain;Pain;Postoperative
rs4680	Efficacy	3	propranolol	Temporomandibular joint dysfunction syndrome
rs4680	Efficacy	3	morphine	Pain
rs4680	Dosage	3	sufentanil
rs4680	Toxicity	3	naloxone;oxycodone	Vomiting
rs4680	Toxicity	3	naloxone;oxycodone	Erythema
rs4680	Toxicity	3	buprenorphine;fentanyl;tramadol	adverse events;Opioid-Related Disorders
rs4680	Efficacy	3	erenumab	Migraine with Aura;Migraine without Aura
rs4680	Efficacy	3	fremanezumab	Migraine with Aura;Migraine without Aura
rs4680	Efficacy	3	galcanezumab	Migraine with Aura;Migraine without Aura
rs4680	Toxicity	3	haloperidol	Schizophrenia
rs4680	Efficacy	3	entacapone	Parkinson Disease
rs4680	Efficacy	3	paroxetine	Major Depressive Disorder
rs4680	Toxicity	3	antipsychotics
rs4680	Efficacy	3	clozapine	Schizophrenia
rs4818	Other	3	opioids	Pain
rs4818	Efficacy	3	quetiapine	Schizophrenia
rs4818	Efficacy	3	risperidone	Schizophrenia
rs5993883	Efficacy	3	quetiapine	Schizophrenia
rs6269	Other	3	opioids	Pain
rs6269	Efficacy	3	quetiapine	Schizophrenia
rs6269	Efficacy	3	morphine
rs6269	Efficacy	3	butorphanol
rs740603	Toxicity	3	methadone	Neonatal Abstinence Syndrome
rs740603	Toxicity	3	buprenorphine	Neonatal Abstinence Syndrome
rs9332377	Toxicity	3	cisplatin	Drug Toxicity;Neoplasms;Ototoxicity
rs9332377	Toxicity	3	cisplatin	Neoplasms;Nephrotoxicity

PharmGKB variants

12 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4633	COMT	3	2.00	5	butorphanol;risperidone;opioids
rs4680	COMT	3	5.00	43	antipsychotics;buprenorphine;methadone;buprenorphine;fentanyl;tramadol;fentanyl;remifentanil;sufentanil;oxycodone;opioids;morphine
rs4818	COMT	3	3.00	3	risperidone;opioids;quetiapine
rs6269	COMT	3	3.00	5	morphine;butorphanol;opioids;quetiapine
rs165599	ARVCF, COMT	3	2.75	2	risperidone;bupropion
rs740603	COMT	3	0.00	2	buprenorphine;methadone
rs933271	COMT, TXNRD2	3	2.50	1	methadone
rs4646316	COMT	3	2.25	2	cisplatin
rs9332377	ARVCF, COMT	3	2.75	2	cisplatin
rs9606186	COMT, TXNRD2	3	2.25	1	risperidone
rs13306278	COMT, TXNRD2	3	2.50	1	Selective serotonin reuptake inhibitors
rs5993883	COMT	3	3.00	1	quetiapine

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

showing 60 of 122 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs4646316	cisplatin	Toxicity	Allele C is associated with increased risk of Ototoxicity when treated with cisplatin in children with Neoplasms as compared to allele T.	PMID:23588304
rs9332377	cisplatin	Toxicity	Allele T is associated with increased risk of Ototoxicity when treated with cisplatin in children as compared to allele C.	PMID:23588304
rs4680	tolcapone	Efficacy	Genotype AG is associated with decreased reaction time when treated with tolcapone in abstinent smokers.	PMID:24095246
rs4680	haloperidol	Toxicity	Genotype AG is associated with increased likelihood of extrapyramidal symptoms when treated with haloperidol in men with Schizophrenia as compared to genotypes AA + GG.	PMID:23963056
rs6269	opioids	Other	Genotypes AG + GG is associated with increased likelihood of requiring postoperative intervention with opioids in children with adenotonsillectomy as compared to genotype AA.	PMID:24533707
rs4633	opioids	Other	Genotypes CC + CT is associated with increased likelihood of requiring postoperative intervention with opioids in children with adenotonsillectomy as compared to genotype TT.	PMID:24533707
rs4818	opioids	Other	Genotypes CG + GG is associated with increased likelihood of requiring postoperative intervention with opioids in children with adenotonsillectomy as compared to genotype CC.	PMID:24533707
rs4680	opioids	Other	Genotypes AG + GG is associated with increased likelihood of requiring postoperative intervention with opioids in children with adenotonsillectomy as compared to genotype AA.	PMID:24533707
rs4680	methylphenidate	Efficacy	Genotypes AA + AG is associated with increased response to methylphenidate in children with Autism Spectrum Disorder as compared to genotype GG.	PMID:23856854
rs4680	“““Analgesics””, ““Antiinflammatory agents, non-steroids””, ““Ergot alkaloids””, ““opioids””, ““sumatriptan”””	Other	Genotype AA is associated with decreased likelihood of Headache Disorders and Substance Withdrawal Syndrome in people not taking Analgesics, Antiinflammatory agents, non-steroids, Ergot alkaloids, opioids and sumatriptan as compared to genotypes AG + GG.	PMID:25096645
rs4646316	cisplatin	Toxicity	Allele C is associated with increased risk of Ototoxicity when treated with cisplatin in children with Neoplasms as compared to allele T.	PMID:25141953
rs9332377	cisplatin	Toxicity	Allele T is associated with increased risk of Ototoxicity when treated with cisplatin in children with Neoplasms as compared to allele C.	PMID:25141953
rs4680	clozapine	Efficacy	Genotype GG is associated with increased response to clozapine in people with Schizophrenia as compared to genotypes AA + AG.	PMID:25560469
rs4680	antipsychotics	Toxicity	Genotypes AA + AG is associated with increased likelihood of Elevated diastolic blood pressure and Elevated systolic blood pressure when treated with antipsychotics in children as compared to genotype GG.	PMID:25048416
rs4680	glucose	Toxicity	Genotypes AA + AG is associated with increased concentrations of glucose in children as compared to genotype GG.	PMID:25048416
rs4680	Drugs used in nicotine dependence	Efficacy	Genotype AA is associated with increased likelihood of cessation when treated with Drugs used in nicotine dependence in people with as compared to genotypes AG + GG.	PMID:26555332
rs6269	quetiapine	Efficacy	Allele A is associated with decreased response to quetiapine in people with Schizophrenia as compared to allele G.	PMID:26282453
rs5993883	quetiapine	Efficacy	Allele T is associated with decreased response to quetiapine in people with Schizophrenia as compared to allele G.	PMID:26282453
rs4818	quetiapine	Efficacy	Allele C is associated with decreased response to quetiapine in people with Schizophrenia as compared to allele G.	PMID:26282453
rs4680	opioids	Dosage	Genotype GG is associated with increased dose of opioids in people with Neoplasms and Pain as compared to genotypes AA + AG.	PMID:28745577
rs4680	opioids	Dosage	Genotype GG is associated with increased dose of opioids in people with Pain, Postoperative as compared to genotype AA.	PMID:25185591
rs4680	morphine	Efficacy	Allele A is associated with increased response to morphine in people with Low Back Pain as compared to allele G.	PMID:23773341
rs4680	morphine	Dosage, Efficacy	Genotype AA is associated with decreased dose of morphine in people with Pain, Postoperative as compared to genotypes AG + GG.	PMID:23686330
rs4680	sufentanil	Dosage, Efficacy	Genotype AA is associated with decreased dose of sufentanil in children as compared to genotypes AG + GG.	PMID:28006928
rs4680	methylphenidate	Efficacy	Genotype GG is associated with increased response to methylphenidate in children with Attention Deficit Disorder with Hyperactivity as compared to genotypes AA + AG.	PMID:29230023
rs4680	morphine, remifentanil	Efficacy	Genotypes AA + AG are associated with increased response to morphine or remifentanil in infants with Pain as compared to genotype GG.	PMID:27027462
rs4680	morphine	Efficacy	Genotype GG is associated with decreased response to morphine in infants with Pain as compared to genotypes AA + AG.	PMID:27027462
rs4680	remifentanil	Efficacy	Genotype AA is associated with increased response to remifentanil in infants with Pain as compared to genotypes AG + GG.	PMID:27027462
rs4680	methylphenidate	Efficacy	Allele G is associated with increased clearance of methylphenidate in children with Attention Deficit Disorder with Hyperactivity as compared to allele A.	PMID:18214865
rs4680	methylphenidate	Efficacy	Genotype GG is associated with increased response to methylphenidate in children with Attention Deficit Disorder with Hyperactivity as compared to genotype AA.	PMID:18214865
rs4680	modafinil	Efficacy	Genotype GG is associated with increased response to modafinil in people with methamphetamine dependence as compared to genotypes AA + AG.	PMID:22217949
rs4680	fentanyl	Toxicity	Genotype AG is associated with increased likelihood of somnolence due to fentanyl in healthy individuals as compared to genotype GG.	PMID:30281924
rs4680	buprenorphine, fentanyl, tramadol	Toxicity	Genotypes AA + GG are associated with increased likelihood of adverse events or Sexual Dysfunctions, Psychological when treated with buprenorphine, fentanyl or tramadol in people with Opioid-Related Disorders as compared to genotype AG.	PMID:30549211
rs4680	buprenorphine, fentanyl, tramadol	Toxicity	Genotype AG is associated with decreased likelihood of Exanthema when treated with buprenorphine, fentanyl or tramadol in people with Opioid-Related Disorders as compared to genotypes AA + GG.	PMID:30549211
rs4680	buprenorphine, fentanyl, tramadol	Toxicity	Genotype AA is associated with increased likelihood of Vomiting when treated with buprenorphine, fentanyl or tramadol in people with Opioid-Related Disorders as compared to genotypes AG + GG.	PMID:30549211
rs4680	buprenorphine, fentanyl, tramadol	Toxicity	Genotype AG is associated with increased likelihood of Exanthema when treated with buprenorphine, fentanyl or tramadol in people with Opioid-Related Disorders as compared to genotypes AA + GG.	PMID:30549211
rs4680	opioids	Dosage	Genotype AG is associated with decreased dose of opioids in children as compared to genotype GG.	PMID:30704436
rs4680	opioids	Efficacy	Genotypes AA + AG are associated with increased response to opioids in children as compared to genotype GG.	PMID:30704436
rs6269	propranolol	Efficacy	Allele G is associated with increased severity of Pain when treated with propranolol in women with Temporomandibular Joint Disorders and Pain as compared to allele A.	PMID:20216107
rs4633	propranolol	Efficacy	Allele C is associated with increased severity of Pain when treated with propranolol in women with Temporomandibular Joint Disorders and Pain as compared to allele T.	PMID:20216107
rs4680	propranolol	Efficacy	Allele G is associated with increased severity of Pain when treated with propranolol in women with Temporomandibular Joint Disorders and Pain as compared to allele A.	PMID:20216107
rs4818	propranolol	Efficacy	Allele G is associated with increased severity of Pain when treated with propranolol in women with Temporomandibular Joint Disorders and Pain as compared to allele C.	PMID:20216107
rs4633	morphine	Dosage, Efficacy	Allele C is associated with increased dose of morphine in people with Pain, Postoperative and Coronary Artery Disease as compared to allele T.	PMID:31967515
rs4680	morphine	Dosage, Efficacy	Allele G is associated with increased dose of morphine in people with Pain, Postoperative and Coronary Artery Disease as compared to allele A.	PMID:31967515
rs4680	mercaptopurine	Toxicity	Allele A is associated with increased risk of Toxic liver disease when treated with mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele G.	PMID:32265697
rs4680	oxycodone	Efficacy	Genotypes AA + AG are associated with increased response to oxycodone as compared to genotype GG.	PMID:31493434
rs4633	opioids	Toxicity	Genotype CT is associated with increased likelihood of Dizziness due to opioids in people with Pain as compared to genotypes CC + TT.	PMID:31745220
rs4633	opioids	Toxicity	Genotype CC is associated with increased likelihood of Sexual Dysfunctions, Psychological due to opioids in women with Pain as compared to genotypes CT + TT.	PMID:31745220
rs933271	methadone	Efficacy	Genotypes CC + CT are associated with increased response to methadone in people with Opioid-Related Disorders as compared to genotype TT.	PMID:32407152
rs4680	opioids	Toxicity	Genotype AG is associated with increased likelihood of Hyperalgesia due to opioids in people with Pain as compared to genotypes AA + GG.	PMID:31041874
rs4680	opioids	Toxicity	Genotype AA is associated with decreased risk of Death due to opioids in people with Opioid-Related Disorders as compared to genotypes AG + GG.	PMID:27061230
rs4680	opioids	Dosage	Genotype GG is associated with increased dose of opioids in women with Breast Neoplasms and Pain, Postoperative as compared to genotypes AA + AG.	PMID:27729204
rs4680	bupropion	Efficacy	Genotypes AG + GG is associated with increased response to bupropion in people with Depressive Disorder, Major as compared to genotype AA.	PMID:32459054
rs4680	opioids	Dosage	Genotypes AA + AG is associated with increased dose of opioids in people with Pain as compared to genotype GG.	PMID:30211780
rs6269	butorphanol	Efficacy	Genotype GG is associated with decreased response to butorphanol in healthy individuals as compared to genotypes AA + AG.	PMID:31806881
rs4633	butorphanol	Efficacy	Genotype CC is associated with decreased response to butorphanol in healthy individuals as compared to genotypes CT + TT.	PMID:31806881
rs4680	morphine, oxycodone	Toxicity	Genotype GG is associated with increased likelihood of somnolence due to morphine or oxycodone in people with Lung Neoplasms as compared to genotypes AA + AG.	PMID:34871222
rs4680	methylphenidate	Toxicity	Allele A is associated with increased likelihood of adverse events when treated with methylphenidate in children with Attention Deficit Disorder with Hyperactivity and Fetal Alcohol Syndrome as compared to allele G.	PMID:35457347
rs4680	naloxone, oxycodone	Toxicity	Genotype AA is associated with increased likelihood of Vomiting when treated with naloxone and oxycodone in people with Pain as compared to genotypes AG + GG.	PMID:35710811
rs4680	naloxone, oxycodone	Toxicity	Genotype GG is associated with increased likelihood of Erythema when treated with naloxone and oxycodone in people with Pain as compared to genotypes AA + AG.	PMID:35710811

PharmGKB dosing guidelines

CPIC / DPWG genotype-guided dosing for this gene (drug × pharmacogene).

3 dosing guidelines:

Guideline	Source	Drug	Dosing?	Recommendation?
Annotation of CPIC Guideline for alfentanil, buprenorphine, codeine, f	CPIC	alfentanil;buprenorphine;codeine;fentanyl;hydrocodone;hydromorphone;levomethadone;morphine;naltrexone;remifentanil;sufentanil;tramadol
Annotation of CPIC Guideline for methadone, oxycodone and COMT, CYP2D6	CPIC	methadone;oxycodone
Annotation of DPWG Guideline for methylphenidate and COMT	DPWG	methylphenidate

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Catecholamine turnover

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
tolcapone	Inhibition	9.54	pKi
opicapone	Inhibition	9.0	pKi
entacapone	Inhibition	8.7	pKi

Binding affinities (BindingDB)

93 measured of 95 human assays (98 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL1089318	KI	1 nM
Isopropyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	1.1 nM
Butyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	1.3 nM
(2-oxo-1,3-dioxol-4-yl)methyl 3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	1.6 nM
Methyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	2.2 nM
(2-amino-3-methylbutanoyloxy)methyl 3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	6 nM
Propyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	9.2 nM
Benzyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	10.2 nM
Butyryloxymethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	10.6 nM
1-(Butyryloxy)ethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	16.6 nM
1-(Isobutyryloxy)ethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	17 nM
Isobutyryloxymethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate	KI	17 nM
ethyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (Example 639) and ethyl (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacrylate (Example 640)	IC50	80 nM	US-20260035341: FTO INHIBITORS
5-hydroxy-2-[3-(4-methoxyphenoxy)phenyl]-3-methylpyrimidin-4-one	IC50	93 nM	US-9260413: Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders
(Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl) acrylonitrile	IC50	120 nM	US-20260035341: FTO INHIBITORS
CHEMBL3425733	IC50	140 nM
CHEMBL3425732	IC50	140 nM
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N,N- dimethylacrylamide	IC50	150 nM	US-20260035341: FTO INHIBITORS
CHEMBL3425731	IC50	160 nM
5-hydroxy-3-methyl-2-(3-phenylphenyl)pyrimidin-4-one	IC50	170 nM	US-9260413: Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders
2-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-3-methylpyrimidin-4-one	IC50	180 nM	US-9260413: Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders
CHEMBL3425741	IC50	180 nM
CHEMBL3425744	IC50	200 nM
5-hydroxy-2-[4-(trifluoromethyl)phenyl]-1,3-diazinan-4-one	IC50	210 nM	US-9260413: Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(2- hydroxybenzyl)-N- methylacrylamide	IC50	330 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N- methoxy-N-methylacrylamide	IC50	350 nM	US-20260035341: FTO INHIBITORS
CHEMBL3425721	IC50	400 nM
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- methylacrylamide	IC50	400 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide	IC50	400 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-5- (trifluoromethyl)benzyl)-3- hydroxy-N-methylacrylamide	IC50	400 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-3-hydroxy-N-(2- hydroxy-3-methylbenzyl)-N- methylacrylamide	IC50	440 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-3- methylbenzyl)-3-hydroxy-N- methylacrylamide	IC50	470 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3-cyano-4,5- dihydroxyphenyl)-N-(2-fluoro-5- methylbenzyl)-3-hydroxy-N- methylacrylamide	IC50	480 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyprop-2-enamide	IC50	500 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3-cyano-4,5- dihydroxyphenyl)-N,N-diethyl-3- hydroxyacrylamide	IC50	500 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-N-(2-fluoro-5- (pyrimidin-4-yl)benzyl)-3-hydroxy- 3-(4-hydroxy-3-methoxy-5- nitrophenyl)-N-methylacrylamide	IC50	500 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-N-(2-fluorobenzyl)-3- hydroxy-3-(4-hydroxy-3-methoxy- 5-nitrophenyl)-N-methylacrylamide	IC50	530 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-4- methylbenzyl)-3-hydroxy-N- methylacrylamide	IC50	530 nM	US-20260035341: FTO INHIBITORS
((Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-4- (pyridin-3-yl)benzyl)-3-hydroxy-N- methylacrylamide	IC50	560 nM	US-20260035341: FTO INHIBITORS
5-hydroxy-2-[3-(2-phenylethynyl)phenyl]-1,3-diazinan-4-one	IC50	590 nM	US-9260413: Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders
US20260035341, Example 5	IC50	600 nM	US-20260035341: FTO INHIBITORS
(Z)-N-(3-(2-chlorophenyl) prop-2- yn-1-yl)-2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl)-3-hydroxy-N- methylacrylamide	IC50	640 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-ethyl-3-hydroxy-N- (2-(pyrimidin-2- yloxy)ethyl)acrylamide	IC50	670 nM	US-20260035341: FTO INHIBITORS
CHEMBL3425729	IC50	680 nM
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-(2-fluoro-3,5- dimethylbenzyl)-3-hydroxy-N- methylacrylamide	IC50	710 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N-((7- fluoroisoquinolin-6-yl) methyl)-3- hydroxy-N-methylacrylamide	IC50	710 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-N-(3-(2- cyanophenyl)propyl)-3-(3,4- dihydroxy-5-nitrophenyl)-N-ethyl- 3-hydroxyacrylamide	IC50	750 nM	US-20260035341: FTO INHIBITORS
US20260035341, Example 658	IC50	800 nM	US-20260035341: FTO INHIBITORS
(Z)-N-(but-2-yn-1-yl)-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)-3- hydroxy-N-methylacrylamide	IC50	820 nM	US-20260035341: FTO INHIBITORS
(Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-oxo-2-(phenylamino) ethyl) acrylamide	IC50	820 nM	US-20260035341: FTO INHIBITORS

ChEMBL bioactivities

169 potent at pChembl≥5 of 198 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	Ki	1	nM	OPICAPONE
8.96	Ki	1.1	nM	CHEMBL1091204
8.89	Ki	1.3	nM	CHEMBL1089630
8.80	Ki	1.6	nM	CHEMBL1091983
8.70	IC50	1.995	nM	CHEMBL4174978
8.70	IC50	1.995	nM	CHEMBL4167128
8.66	Ki	2.2	nM	CHEMBL1089504
8.50	IC50	3.162	nM	CHEMBL4170443
8.40	IC50	3.981	nM	CHEMBL4171117
8.40	IC50	3.981	nM	CHEMBL4172614
8.22	Ki	6	nM	CHEMBL1091982
8.20	IC50	6.31	nM	CHEMBL4169861
8.20	IC50	6.31	nM	CHEMBL4177089
8.20	IC50	6.3	nM	CHEMBL4462175
8.10	IC50	7.943	nM	CHEMBL4160303
8.04	Ki	9.2	nM	CHEMBL1089505
8.00	Ki	10	nM	OPICAPONE
8.00	IC50	10	nM	CHEMBL4163421
8.00	IC50	10	nM	CHEMBL4461693
8.00	IC50	10	nM	CHEMBL4470211
7.99	Ki	10.2	nM	CHEMBL1089536
7.97	Ki	10.6	nM	CHEMBL1089539
7.89	IC50	13	nM	CHEMBL4458006
7.80	IC50	16	nM	CHEMBL4531460
7.78	Ki	16.6	nM	CHEMBL1091981
7.77	Ki	17	nM	CHEMBL1089538
7.77	Ki	17	nM	CHEMBL1089537
7.70	IC50	19.95	nM	CHEMBL4174102
7.70	IC50	19.95	nM	CHEMBL4176008
7.70	IC50	19.95	nM	CHEMBL4174117
7.62	IC50	24	nM	CHEMBL4563060
7.48	IC50	33	nM	CHEMBL4464343
7.46	IC50	35	nM	CHEMBL3798524
7.42	IC50	38	nM	CHEMBL4449462
7.40	IC50	40	nM	CHEMBL3799913
7.40	IC50	40	nM	CHEMBL4453736
7.40	IC50	40	nM	CHEMBL4583818
7.40	IC50	40	nM	CHEMBL4447751
7.33	IC50	47	nM	CHEMBL3425734
7.30	IC50	49.5	nM	CHEMBL3799623
7.30	IC50	50.12	nM	CHEMBL4162990
7.30	IC50	50	nM	CHEMBL4476127
7.30	IC50	50	nM	CHEMBL4523002
7.28	IC50	53	nM	CHEMBL3425735
7.27	IC50	54	nM	CHEMBL3818719
7.26	IC50	55	nM	CHEMBL3800198
7.24	IC50	57	nM	CHEMBL3425740
7.22	IC50	60	nM	CHEMBL4556206
7.22	IC50	60	nM	ENTACAPONE
7.21	IC50	61	nM	CHEMBL3425738

PubChem BioAssay actives

106 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Opicapone	1153918: Inhibition of catalytic activity of human cloned COMT expressed in Escherichia coli using [3H]-S-adenosylmethionine as substrate after 20 mins by liquid scintillation counting	ki	0.0010	uM
3-chloro-5,6-dihydroxy-7-nitro-1-benzothiophene-2-carboxylic acid	474552: Inhibition of human recombinant COMT by microplate screening assay	ki	0.0010	uM
5-cyclopentylsulfonyl-7-fluoroquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0020	uM
5-(2-benzylpyrrolidin-1-yl)sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0020	uM
5-[3-(4-fluorophenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0032	uM
7-fluoro-5-(4-fluorophenyl)sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0040	uM
7-fluoro-5-pyrrolidin-1-ylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0040	uM
5-cyclopentylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0063	uM
7-fluoro-5-(4-methylphenyl)sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0063	uM
2-[(2,6-dimethylphenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0063	uM
5-pyrrolidin-1-ylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0079	uM
7-chloro-5-pyrrolidin-1-ylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0100	uM
2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0100	uM
2-[(2,6-dichlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0100	uM
2-[(2,4-dimethylphenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0130	uM
2-[(2-chloro-6-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0160	uM
7-chloro-5-cyclopentylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0199	uM
7-methyl-5-pyrrolidin-1-ylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0199	uM
2-[(2,6-difluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0380	uM
2-[(2-chlorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0400	uM
2-[(2-chloro-4-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0400	uM
2-[(2,3-dimethylphenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0400	uM
1-[4-(1-benzylpyrazol-4-yl)-2-pyridinyl]-3-hydroxypyridin-4-one	1298723: Inhibition of recombinant human C-terminal His6-tagged MB-COMT expressed in Bacmid using SAM/dopamine as substrate preincubated for 2 hrs followed by substrate addition measured after 25 mins by SAC TAMRA tracer-based fluorescence polarization assay	ic50	0.0495	uM
7-hydroxy-2-[(2-methylphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0500	uM
2-[(2-fluorophenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0500	uM
5-ethylsulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0501	uM
2-N,2-N,3-N,3-N-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide	1308078: Inhibition of human recombinant His-tagged soluble COMT expressed in Escherichia coli BL21 using aesculetin as substrate after 60 mins by microplate assay in presence of SAM	ic50	0.0540	uM
5-hydroxy-2-(1-hydroxybutyl)-1-(3-phenylphenyl)pyridin-4-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.0570	uM
7-hydroxy-2-[[2-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0600	uM
2-[(2,5-dimethylphenyl)methyl]-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.0630	uM
5-[4-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0631	uM
(E)-1-(3,4-dihydroxy-5-nitrophenyl)-3-(3-methoxyphenyl)prop-2-en-1-one	1659946: Inhibition of COMT (unknown origin)	ic50	0.0700	uM
5-[5-[1-(4-methoxyphenyl)cyclopropyl]-1H-pyrazol-3-yl]-2,4-dimethyl-1,3-thiazole	1679183: Inhibition of recombinant wild-type human COMT expressed in Escherichia coli BL21 using 4-nitrocatechol-Alexa488 as substrate in presence of cofactor SAM preincubated for 1 min followed by substrate addition and measured every 60 sec up to 180 times by fluorescence based microtiter plate reader analysis	ic50	0.0750	uM
7-fluoro-5-[4-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.0794	uM
5-hydroxy-2-[hydroxy(phenyl)methyl]-1-(3-phenylphenyl)pyridin-4-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.0880	uM
2-[(7-hydroxy-8-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2-yl)methyl]benzonitrile	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.1000	uM
5-hydroxy-2-(hydroxymethyl)-1-(4-phenylphenyl)pyridin-4-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.1400	uM
5-hydroxy-2-(hydroxymethyl)-1-(3-phenylphenyl)pyridin-4-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.1400	uM
1-(4-butylphenyl)-5-hydroxy-2-(hydroxymethyl)pyridin-4-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.1600	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148113: Binding affinity to human COMT incubated for 45 mins by Kinobead based pull down assay	kd	0.1693	uM
(5E)-5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-3-ethyl-1,3-thiazolidine-2,4-dione	1308078: Inhibition of human recombinant His-tagged soluble COMT expressed in Escherichia coli BL21 using aesculetin as substrate after 60 mins by microplate assay in presence of SAM	ic50	0.1790	uM
5-hydroxy-2-(1-hydroxy-2-methylpropyl)-1-(3-phenylphenyl)pyridin-4-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.1800	uM
7-chloro-5-(4-fluorophenyl)sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.1995	uM
2,4-dimethyl-5-[5-(1-phenylcyclopropyl)-1H-pyrazol-3-yl]-1,3-thiazole	1679183: Inhibition of recombinant wild-type human COMT expressed in Escherichia coli BL21 using 4-nitrocatechol-Alexa488 as substrate in presence of cofactor SAM preincubated for 1 min followed by substrate addition and measured every 60 sec up to 180 times by fluorescence based microtiter plate reader analysis	ic50	0.2100	uM
2-benzyl-7-hydroxy-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.2200	uM
7-hydroxy-2-[(2-methoxyphenyl)methyl]-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-8-one	1611900: Inhibition of human MB-COMT expressed in HEK293 cells using dopamine as substrate and SAM as cofactor preincubated for 30 mins followed by substrate addition and measured after 40 mins by HTRF assay	ic50	0.2500	uM
5-(4-methylphenyl)quinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.2512	uM
(E)-3-(3-bromophenyl)-1-(3,4-dihydroxy-5-nitrophenyl)prop-2-en-1-one	1659946: Inhibition of COMT (unknown origin)	ic50	0.2900	uM
7-chloro-5-(4-methylphenyl)sulfonylquinolin-8-ol	1363208: Inhibition of c-terminal hexa-His tagged human MB-COMT expressed in HEK293 cell membrane homogenate using norepinephrine as substrate after 1 hr in presence of SAM by MTase glo methyltransferase assay	ic50	0.3162	uM
9-hydroxy-6H-pyrido[2,1-c][1,4]benzothiazin-8-one	1205874: Inhibition of C-terminal His6-tagged recombinant human membrane bound COMT expressed in Bacmid infected Sf-9 insect cells using dopamine/SAM as substrate/cofactor preincubated for 2 hrs followed by dopamine/SAM addition after 25 mins by fluorescence polarization assay	ic50	0.4000	uM

CTD chemical–gene interactions

161 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tolcapone	decreases reaction, increases methylation, decreases activity, increases abundance, decreases abundance	15
Levodopa	affects response to substance, increases methylation, decreases reaction, decreases activity, increases abundance	11
Estradiol	decreases abundance, increases methylation, decreases expression, affects cotreatment, affects binding (+4 more)	8
bisphenol A	increases expression, increases methylation, decreases reaction, decreases expression	5
Dopamine	decreases reaction, increases methylation, decreases activity, increases abundance	5
Fulvestrant	decreases expression, decreases reaction, increases expression	4
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	4
entacapone	decreases reaction, increases methylation, decreases activity, increases abundance	3
Estrogens	affects metabolic processing, decreases expression	3
Hydrogen Peroxide	decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	3
Genistein	increases methylation, affects binding, increases reaction, decreases activity, decreases expression (+1 more)	3
2-hydroxyestradiol	affects metabolic processing, increases methylation	2
daidzein	decreases expression, decreases reaction, increases methylation, decreases activity	2
4-hydroxyestradiol	increases methylation, decreases reaction, affects metabolic processing	2
cobaltous chloride	decreases expression	2
catechol	affects cotreatment, decreases reaction, increases expression, increases abundance, increases response to substance (+1 more)	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Estrogens, Catechol	decreases metabolic processing, decreases activity, increases methylation	2
Epinephrine	increases methylation, decreases activity, increases abundance	2
Mercury	affects response to substance	2
Methamphetamine	affects response to substance, increases response to substance	2
Methyldopa	increases methylation, decreases activity	2
Norepinephrine	increases methylation, decreases activity, increases abundance	2
Smoke	decreases expression	2
3,4-Dihydroxyphenylacetic Acid	decreases activity, increases abundance, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
perfluorodecanesulfonic acid	increases expression	1

ChEMBL screening assays

55 unique, capped per target: 47 binding, 8 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1007121	Binding	Inhibition of catechol-O-methyl transferase at 10 uM	Discovery of benzoylpiperazines as a novel class of potent and selective GlyT1 inhibitors. — *Bioorg Med Chem Lett*
CHEMBL3541531	ADMET	Drug metabolism in human liver cytosol assessed as COMT-mediated methylation after 10 to 30 mins by HPLC analysis in presence of SAM	Comparison of metabolism of sesamin and episesamin by drug-metabolizing enzymes in human liver. — *Drug Metab Dispos*

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2UW	Abcam HEK293T COMT KO	Transformed cell line	Female
CVCL_E7ND	KOLF2.1J COMT 21.8kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_SJ49	HAP1 COMT (-) 1	Cancer cell line	Male
CVCL_SJ50	HAP1 COMT (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 160 trials:

NCT	Phase	Status	Title
NCT00374465	Phase 4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	Phase 4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	Phase 4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	Phase 4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	Phase 4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	Phase 4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00333827	Phase 3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	Phase 3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	Phase 3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	Phase 3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	Phase 3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	Phase 3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	Phase 3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	Phase 3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	Phase 3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	Phase 3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00629018	Phase 2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	Phase 2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	Phase 2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	Phase 2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery
NCT01020968	Phase 2	COMPLETED	Use of Ixmyelocel-T (Formerly Catheter-based Cardiac Repair Cell [CRC]) Treatment in Patients With Heart Failure Due to Dilated Cardiomyopathy
NCT01302171	Phase 2	COMPLETED	Bone Marrow Derived Adult Stem Cells for Dilated Cardiomyopathy
NCT01350310	Phase 2	COMPLETED	Safety and Efficacy Study of Intramyocardial Stem Cell Therapy in Patients With Dilated Cardiomyopathy
NCT02133911	Phase 2	COMPLETED	A Pilot Trial of Ranolazine to Treat Patients With Dilated Cardiomyopathy
NCT03071653	Phase 2	SUSPENDED	Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study
NCT03572660	Phase 2	ACTIVE_NOT_RECRUITING	Use of Bone Marrow Derived Stem Cell and G-CSF With Circulatory Assistance in the Treatment of DCM
NCT03775070	Phase 2	COMPLETED	Simvastatin Therapy in Patients With Dilated Cardiomyopathy.
NCT04405804	Phase 2	UNKNOWN	Early Administration of Ivabradine in Children With Heart Failure
NCT05410873	Phase 2	COMPLETED	Examining the Effects of Mitochondrial Oxidative Stress in DCM
NCT06632834	Phase 2	RECRUITING	Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation
NCT00585546	Phase 1	TERMINATED	Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure
NCT02293603	Phase 1	UNKNOWN	Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC)
NCT03062956	Phase 1	COMPLETED	A Single Ascending Dose Study Assessing the Safety, Tolerability, PK and PD of MYK-491
NCT03129568	Phase 1	COMPLETED	Transcoronary Infusion of Cardiac Progenitor Cells in Pediatric Dilated Cardiomyopathy
NCT04982081	Phase 1	UNKNOWN	Treating Congestive HF With hiPSC-CMs Through Endocardial Injection
NCT06381466	Phase 1	TERMINATED	A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral AZD0233 Compared With Placebo in Healthy Adult Participants.
NCT06464588	Phase 1	RECRUITING	A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)
NCT07137338	Phase 1	RECRUITING	A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in Subjects With BAG3 Dilated Cardiomyopathy
NCT07241104	Phase 1	RECRUITING	A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy
NCT07516288	Phase 1	RECRUITING	Safety and Efficacy of Second Infusion of FAP iCDC in End-stage Dilated Cardiomyopathy
NCT06701851	Not specified	RECRUITING	Neural Correlates of Movement Disorders Associated With PRRT2 Related Paroxysmal Kinesigenic Dyskinesia - an Ancillary Study of AMEDYST Research
NCT00743639	Phase 2/3	COMPLETED	Autologous Transplantation of Bone Marrow Mononuclear Stem-Cells for Dilated Cardiomyopathy
NCT01311791	Phase 2/3	COMPLETED	A Randomized, Controlled Study to Evaluate Algisyl-LVR™ as a Method of Left Ventricular Augmentation for Heart Failure
NCT02248532	Phase 2/3	COMPLETED	Repetitive Intramyocardial CD34+ Cell Therapy in Dilated Cardiomyopathy (REMEDIUM)
NCT02652728	Phase 2/3	UNKNOWN	Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy
NCT02654678	Phase 2/3	UNKNOWN	Follow-up Safety Trial in Children With Chronic Heart Failure Therapy Receiving Orodispersible Minitablets of Enalapril
NCT00454818	Phase 1/2	COMPLETED	Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure
NCT00615394	Phase 1/2	COMPLETED	Autologous Transplantation of Bone Marrow Mononuclear Stem-Cells by Mini-Thoracotomy
NCT01219452	Phase 1/2	UNKNOWN	Intramuscular Injection of Mesenchymal Stem Cell for Treatment of Children With Idiopathic Dilated Cardiomyopathy
NCT01290822	Phase 1/2	TERMINATED	Optimized Biventricular Pacing Allograft Recipients
NCT01739777	Phase 1/2	COMPLETED	Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy
NCT03447990	Phase 1/2	COMPLETED	v4 Study Evaluating the Safety, Tolerability and Preliminary Pharmacokinetics and Pharmacodynamics of MYK-491
NCT06902896	Phase 1/2	RECRUITING	Safety and Efficacy of FAP iCDC in End-stage Dilated Cardiomyopathy
NCT07347197	Phase 1/2	NOT_YET_RECRUITING	Endocardial Delivery for Myocardial Regeneration Using Allogeneic iPSC-derived Cardiomyocyte Spheroids for HF With Systolic Dysfunction (EMERALD Study)
NCT07426419	Phase 1/2	RECRUITING	An AAV Gene Therapy Trial of AFTX-201 in Adults With BAG3-Associated Dilated Cardiomyopathy (DCM)
NCT05837143	Early Phase 1	UNKNOWN	Myocardial Telomere Recapping Study for Dilated Cardiomyopathy
NCT00001313	Not specified	COMPLETED	Evaluation of Patients With Known or Suspected Heart Disease
NCT00180323	Not specified	COMPLETED	ACC - Atrial Contribution to CRT
NCT00208806	Not specified	COMPLETED	Resynchronization Therapy in Young Patients With and Without CHD
NCT00282789	Not specified	COMPLETED	BiPAP for Cardiomyopathy With Central Sleep Apnea

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for COMT across ~30M SureChEMBL compounds — explore on Sugi Predict.