ADM2

Summary

ADM2 (adrenomedullin 2, HGNC:28898) is a protein-coding gene on chromosome 22q13.33, encoding Protein ADM2 (Q7Z4H4). Intermedin/ADM2 is a peptide hormone that plays a role as physiological regulator of gastrointestinal and cardiovascular bioactivities mediated by the CALCRL-RAMPs receptor complexes.

This gene encodes a member of the calcitonin gene-related peptide (CGRP)/calcitonin family of hormones that play a role in the regulation of cardiovascular homeostasis, prolactin release, anti-diuresis, anti-natriuresis, and regulation of food and water intake. The encoded protein is proteolytically processed to generate one or more biologically active peptides.

Source: NCBI Gene 79924 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 59 total — 9 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001253845

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28898
Approved symbol	ADM2
Name	adrenomedullin 2
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Aliases	AM2, FLJ21135
Ensembl gene	ENSG00000128165
Ensembl biotype	protein_coding
OMIM	608682
Entrez	79924

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000395737, ENST00000395738

RefSeq mRNA: 2 — MANE Select: NM_001253845 NM_001253845, NM_001369882

CCDS: CCDS33682

Canonical transcript exons

ENST00000395737 — 3 exons

Exon	Start	End
ENSE00001436105	50481837	50481957
ENSE00001522660	50482567	50486437
ENSE00001522661	50481543	50481763

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 79.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.8400 / max 99.3389, expressed in 1171 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193000	3.2235	1012
193001	1.5441	648
193002	1.0724	467

Top tissues by expression

265 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	79.86	gold quality
body of pancreas	UBERON:0001150	78.77	gold quality
gluteal muscle	UBERON:0002000	78.41	gold quality
triceps brachii	UBERON:0001509	78.34	gold quality
buccal mucosa cell	CL:0002336	78.27	gold quality
orbitofrontal cortex	UBERON:0004167	77.00	gold quality
vena cava	UBERON:0004087	76.95	gold quality
body of tongue	UBERON:0011876	76.71	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	76.69	gold quality
cardia of stomach	UBERON:0001162	76.46	gold quality
medial globus pallidus	UBERON:0002477	76.43	gold quality
pylorus	UBERON:0001166	76.25	gold quality
pericardium	UBERON:0002407	76.23	gold quality
pharyngeal mucosa	UBERON:0000355	76.18	gold quality
vastus lateralis	UBERON:0001379	76.13	gold quality
left lobe of thyroid gland	UBERON:0001120	76.05	gold quality
tongue	UBERON:0001723	75.97	gold quality
subthalamic nucleus	UBERON:0001906	75.88	gold quality
inferior vagus X ganglion	UBERON:0005363	75.87	gold quality
substantia nigra pars compacta	UBERON:0001965	75.79	gold quality
superior surface of tongue	UBERON:0007371	75.68	gold quality
ventral tegmental area	UBERON:0002691	75.67	gold quality
saphenous vein	UBERON:0007318	75.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	75.52	gold quality
nipple	UBERON:0002030	75.43	gold quality
lateral nuclear group of thalamus	UBERON:0002736	75.43	gold quality
quadriceps femoris	UBERON:0001377	75.32	gold quality
pons	UBERON:0000988	75.19	gold quality
trachea	UBERON:0003126	75.19	gold quality
thyroid gland	UBERON:0002046	75.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
FLT1	Activation
KDR	Activation
VEGFA	Activation

Upstream regulators (CollecTRI, top): HIF1A

Literature-anchored findings (GeneRIF, showing 40)

• Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes (PMID:14615490)
• ADM2 may be related to the central and peripheral regulation of the circulation and water-electrolyte metabolism (PMID:16359754)
• IMD expressed by pericytes in has a role in susceptibility of the skin of atopic dermatitis patients to inflammatory stimuli (PMID:17008878)
• Study has shown expression of AM2/IMD in various types of cells in the central nervous system and the cardiovascular system, and suggested possible (patho)physiological roles of AM2/IMD in these systems. (PMID:17346853)
• robust increase in expression of the peptide in hypertrophied and ischaemic myocardium indicates an important protective role for adrenomedullin 2 as an endogenous counter-regulatory peptide in the heart–REVIEW (PMID:17965749)
• adrenomedullin 2/intermedin may have autocrine/paracrine regulatory roles in adrenal tumors and attached non-neoplastic adrenal tissues, such as tumor growth. (PMID:18460550)
• Vascular injury in rat kidney is reduced by IMD gene delivery and it prevents glomerular and peritubular capillary loss. (PMID:18829738)
• Data show that adrenomedullin-2 was shown to be secreted by HAEC and may play a potential protective role in human aortic endothelial cells. (PMID:19255504)
• may have a role in the physiology of human pregnancy via regulation of trophoblast invasion and migration (PMID:19535789)
• IMD enhances angiogenesis through ERK, Akt/NOS/NO, and VEGF/VEGFR-2 signaling pathways (PMID:19592612)
• IMD is a novel hypoxia-induced gene and a potential interventional agent for the improvement of endothelial barrier function in systemic inflammatory responses and hypoxia-induced vascular leakage. (PMID:19684198)
• IMD may be an endogenous vasoprotective factor for vascular calcification (PMID:19910445)
• potentially involved in regulating HLA-G antigen at the maternal-fetal interface and facilitating trophoblast invasion and migration via MAPK3/1 phosphorylation (PMID:21816853)
• Intermedin reduces HUVEC permeability via Rac1-mediated actin cytoskeleton rearrangement. (PMID:21816966)
• adm2 polymorphism is associated with renal dysfunction, blood pressure regulation and asymptomatic cerebrovascular diseases in the Japanese general population (PMID:21832999)
• Adrenomedullin-related peptide, AM2 was highly expressed in colorectal cancer tissue. The percent increase of AM2 synthesis in cancer tissues to the surrounding normal tissues was greater than adrenomedullin. (PMID:21839130)
• Data showed that intermedin (IMD)/adrenomedullin 2 (ADM2) is a novel oocyte-derived ligand important for the regulation of cell interactions in COCs that functions, in part, by suppressing cumulus cell apoptosis. (PMID:22009752)
• Intermedin plays a critical role in the vascular remodeling process and tumor angiogenesis by regulating vascular endothelial-cadherin and extracellular signal-regulated kinase. (PMID:22922959)
• this study is the first to demonstrate a potential involvement of IMD in human embryo implantation and placental development via regulation of trophoblast invasion at the maternal-fetal interface (PMID:23337723)
• Plasma intermedin and BNP levels were markedly higher in acute coronary syndrome patients than in healthy people. (PMID:23391507)
• a significant increase in plasma intermedin following acute myocardial infarction may be associated with oxidative stress, and could be used as a marker to reflect the severity of the coronary stenosis (PMID:23499766)
• ADM and IMD mRNA expression are elevated in chronic heart failure at different stages of the disease. (PMID:24531032)
• results suggest that high plasma intermedin level is associated with poor outcomes of patients and may be a useful prognostic biomarker in ST-segment elevation acute myocardial infarction. (PMID:24969626)
• TSH induced AM2/IMD expression in the thyroid gland and it could locally work as a potent vasodilator, resulting in the expansion of thyroid inter-follicular capillaries. (PMID:25102228)
• Intermedin affects the endothelial cell junction and blood vessel sprouting in a VE-cadherin dependent way. (PMID:25637664)
• High levels of ADM2 expression predict a poorer survival in patients with pancreatic adenocarcinoma. (PMID:25982376)
• Elevated plasma intermedin levels are independently associated with long-term recurrence and distant metastasis of prostate cancer. (PMID:26406405)
• ADM2 may contribute to the physiology of embryo implantation and placental growth via increasing MMP2 and decreasing MUC1 expression to facilitate trophoblast invasion. (PMID:26510869)
• Intermedin (IMD) derived from human cardiac microvascular endothelial cell and acting in a paracrine manner on cardiomyocytes, predominantly at AM1 receptors, is more likely to contribute to direct protection by endogenous IMD of cardiomyocytes against acute ischemia reperfusion injury. (PMID:26743504)
• Intermedin1-53 may attenuate vascular calcification by upregulating alpha-Klotho via the calcitonin receptor/modifying protein complex and protein kinase A signaling. (PMID:26880455)
• ADM-2 is a stress-inducible gene controlled by ATF-4. (PMID:27328454)
• Mouse and human heart valves expressed mRNAs for the CRL ligands adrenomedullin (AM), adrenomedullin-2 (AM-2) and calcitonin gene-related peptide (CGRP) and for their receptor components, i.e., CRL and receptor-activity-modifying proteins 1-3. (PMID:27553639)
• The plasma ADM2 levels were inversely correlated with obesity in humans, and adipo-ADM2-transgenic (tg) mice displayed resistance to high-fat diet-induced obesity with increased energy expenditure. (PMID:27621315)
• IMD may be an important self-protective factor in response to sepsis. (PMID:29980671)
• Intermedin binds the RAMP1/CLR complex via a triple beta-turn. (PMID:30139742)
• Study revealed that exogenous intermedin up-regulates the expression of VEGF and RAMP2 at least partially via activating Wnt/beta-catenin signaling, finally promoting angiogenesis of hypoxia and reoxygenation impaired HUVECs in vitro. (PMID:30931679)
• Consistent with this hypothesis, we showed that acylated truncated ADM/ADM2 analogs of 27-31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. (PMID:31150417)
• AM2 signaling is suppressed in adipose tissue in obesity, involving lower receptor expression and ligand availability, likely contributing to insulin resistance and other aspects of the pathophysiology associated with obesity. (PMID:31642491)
• Protective effects of intermedin/adrenomedullin-2 in a cellular model of human pulmonary arterial hypertension. (PMID:32017948)
• Intermedin alleviates the inflammatory response and stabilizes the endothelial barrier in LPS-induced ARDS through the PI3K/Akt/eNOS signaling pathway. (PMID:32892076)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adm2a	ENSDARG00000045708
mus_musculus	Adm2	ENSMUSG00000054136
rattus_norvegicus	Adm2	ENSRNOG00000089041

Paralogs (1): ADM (ENSG00000148926)

Protein

Protein identifiers

Protein ADM2 — Q7Z4H4 (reviewed: Q7Z4H4)

Alternative names: Intermedin

All UniProt accessions (1): Q7Z4H4

UniProt curated annotations — full annotation on UniProt →

Function. Intermedin/ADM2 is a peptide hormone that plays a role as physiological regulator of gastrointestinal and cardiovascular bioactivities mediated by the CALCRL-RAMPs receptor complexes. Activates the cAMP-dependent pathway through interaction with CALCRL-RAMP3 receptor complex.

Subcellular location. Secreted.

Tissue specificity. Expressed in the esophagus, stomach, jejunum, ileum, ileocecum, ascending colon, transverse colon, descending colon and rectum. Expressed in myocardial cells of the heart, renal tubular cells, hypothalamus, and pituitary.

Similarity. Belongs to the adrenomedullin family.

RefSeq proteins (2): NP_001240774, NP_001356811 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR051665	Adrenomedullin-reg_peptide	Family

UniProt features (13 total): site 3, peptide 2, region of interest 2, signal peptide 1, propeptide 1, disulfide bond 1, helix 1, strand 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6D1U	X-RAY DIFFRACTION	2.05
6UVA	ELECTRON MICROSCOPY	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z4H4-F1	58.44	0.00

Antibody-complex structures (SAbDab): 1 — 6UVA

Functional residue map

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

Catalytic / active sites (3): 107 (required for calcrl receptor interaction); 114 (required for calcrl receptor interaction); 119 (required for calcrl receptor interaction)

Post-translational modifications (1): 147

Disulfide bonds (1): 110–115

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-419812	Calcitonin-like ligand receptors
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 87 (showing top): GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_HEART_RATE, GOBP_REGULATION_OF_HEART_RATE, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_REGULATION_OF_URINE_VOLUME, GOBP_NEGATIVE_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_SYSTEM_PROCESS, TGGNNNNNNKCCAR_UNKNOWN, GOBP_HEART_PROCESS, GOBP_POSITIVE_REGULATION_OF_BLOOD_CIRCULATION

GO Biological Process (10): angiogenesis (GO:0001525), regulation of systemic arterial blood pressure (GO:0003073), protein phosphorylation (GO:0006468), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), feeding behavior (GO:0007631), positive regulation of heart rate (GO:0010460), positive regulation of gene expression (GO:0010628), positive regulation of angiogenesis (GO:0045766), negative regulation of blood pressure (GO:0045776), adrenomedullin receptor signaling pathway (GO:1990410)

GO Molecular Function (2): hormone activity (GO:0005179), protein-containing complex binding (GO:0044877)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of blood pressure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
phosphorylation	1
protein modification process	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
behavior	1
regulation of heart rate	1
positive regulation of heart contraction	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
calcitonin family receptor signaling pathway	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

546 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADM2	CALCRL	Q16602	985
ADM2	RAMP3	O60896	923
ADM2	RAMP1	O60894	922
ADM2	ADM	P35318	881
ADM2	RAMP2	O60895	880
ADM2	MIOX	Q9UGB7	794
ADM2	ADM5	C9JUS6	790
ADM2	AKR1B10	O60218	763
ADM2	AKR1A1	P14550	761
ADM2	IAPP	P10997	719
ADM2	TAP2	Q03519	710
ADM2	MAPK8IP2	Q13387	677
ADM2	PARVB	Q9HBI1	672
ADM2	TAP1	Q03518	670
ADM2	CALCB	P10092	667

IntAct

0 interactions, top by confidence:

BioGRID (2): ADM2 (Reconstituted Complex), ADM2 (Affinity Capture-RNA)

ESM2 similar proteins: B0VXV8, B8K1V9, D1MZV3, D5J9S0, D9IX97, O46540, O77559, P01021, P01142, P01143, P01160, P05125, P06296, P07499, P0C7P5, P0C7P6, P12272, P13085, P16860, P18104, P22858, P23582, P27596, P52211, P55206, P55207, P56283, P56469, P61312, P68515, P79799, P83228, P84715, P97297, Q09GK2, Q27J49, Q2PE51, Q2XXL8, Q61839, Q62949

Diamond homologs: P61312, Q7TNK8, Q7Z4H4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	1
Uncertain significance	42
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
152914	GRCh38/hg38 22q13.2-13.33(chr22:42837094-50735806)x1	Pathogenic
1808266	GRCh37/hg19 22q13.31-13.33(chr22:44390702-51137629)x1	Pathogenic
223118	Single allele	Pathogenic
2423149	NC_000022.10:g.(?50167881)(51066207_?)del	Pathogenic
2425301	NC_000022.10:g.(?50297486)(51066207_?)del	Pathogenic
253559	GRCh37/hg19 22q13.1-13.33(chr22:40425714-51220961)x3	Pathogenic
57674	GRCh38/hg38 22q13.31-13.33(chr22:47122613-50739836)x1	Pathogenic
816570	GRCh37/hg19 22q13.32-13.33(chr22:48454469-51144947)x3	Pathogenic
976873	NC_000022.11:g.46467175_50759338del	Pathogenic
626295	Single allele	Likely pathogenic

SpliceAI

138 predictions. Top by Δscore:

Variant	Effect	Δscore
22:50481955:CAGG:C	donor_loss	1.0000
22:50481957:GGTG:G	donor_loss	1.0000
22:50481953:CCCAG:C	donor_gain	0.9900
22:50481958:G:GG	donor_gain	0.9900
22:50481954:CCAG:C	donor_gain	0.9800
22:50481955:CAG:C	donor_gain	0.9800
22:50481956:AG:A	donor_gain	0.9800
22:50481957:GG:G	donor_gain	0.9800
22:50486239:T:TA	acceptor_gain	0.9800
22:50482561:CTGCA:C	acceptor_loss	0.9400
22:50482563:GCAG:G	acceptor_loss	0.9400
22:50482564:CAG:C	acceptor_loss	0.9400
22:50482565:A:C	acceptor_loss	0.9400
22:50482566:G:GT	acceptor_loss	0.9400
22:50486256:C:A	acceptor_gain	0.9200
22:50482565:AG:A	acceptor_gain	0.9100
22:50482566:GG:G	acceptor_gain	0.9100
22:50482566:GGGA:G	acceptor_gain	0.9100
22:50482565:A:AG	acceptor_gain	0.9000
22:50482566:G:GG	acceptor_gain	0.9000
22:50482565:AGG:A	acceptor_gain	0.8900
22:50482566:GGG:G	acceptor_gain	0.8900
22:50482564:CAGGG:C	acceptor_gain	0.8700
22:50482565:AGGGA:A	acceptor_gain	0.8700
22:50482566:GGGAG:G	acceptor_gain	0.8700
22:50482659:C:T	donor_gain	0.8700
22:50482636:G:GT	donor_gain	0.8600
22:50482556:T:A	acceptor_loss	0.8400
22:50482632:TCTGG:T	donor_gain	0.8400
22:50482562:T:TA	acceptor_gain	0.8100

AlphaMissense

927 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:50481884:A:C	S13R	0.984
22:50481886:C:A	S13R	0.984
22:50481886:C:G	S13R	0.984
22:50482800:G:A	C115Y	0.983
22:50482784:T:C	C110R	0.980
22:50482785:G:A	C110Y	0.980
22:50482799:T:C	C115R	0.978
22:50482892:A:C	S146R	0.978
22:50482894:C:A	S146R	0.978
22:50482894:C:G	S146R	0.978
22:50482883:A:C	S143R	0.975
22:50482885:C:A	S143R	0.975
22:50482885:C:G	S143R	0.975
22:50482784:T:A	C110S	0.974
22:50482785:G:C	C110S	0.974
22:50482799:T:A	C115S	0.973
22:50482800:G:C	C115S	0.973
22:50482817:A:C	S121R	0.972
22:50482819:C:A	S121R	0.972
22:50482819:C:G	S121R	0.972
22:50482800:G:T	C115F	0.971
22:50482815:T:A	L120H	0.971
22:50482815:T:C	L120P	0.970
22:50482824:G:C	R123P	0.970
22:50482899:G:A	G148D	0.967
22:50482831:G:C	W125C	0.966
22:50482831:G:T	W125C	0.966
22:50482801:C:G	C115W	0.965
22:50482785:G:T	C110F	0.963
22:50482786:T:G	C110W	0.963

dbSNP variants (sampled 300 via entrez): RS1000347587 (22:50485686 G>A), RS1000386044 (22:50481587 G>A,T), RS1000400122 (22:50482969 C>G), RS1000438518 (22:50481433 C>G), RS1000782721 (22:50485475 T>C,G), RS1001086298 (22:50484698 C>T), RS1001100687 (22:50479709 G>A,C,T), RS1001174425 (22:50480467 G>A), RS1001437603 (22:50480786 G>A), RS1001630329 (22:50481221 C>T), RS1001688711 (22:50485007 T>C), RS1001949463 (22:50480570 T>A,C,G), RS1001959330 (22:50480312 G>A,C), RS1002113353 (22:50484405 G>A), RS1002181517 (22:50485161 T>C)

Disease associations

OMIM: gene MIM:608682 | disease phenotypes: MIM:606232

GenCC curated gene-disease

Mondo (3): autism spectrum disorder (MONDO:0005258), metachromatic leukodystrophy (MONDO:0018868), Phelan-McDermid syndrome (MONDO:0011652)

Orphanet (3): Metachromatic leukodystrophy (Orphanet:512), Phelan-McDermid syndrome (Orphanet:48652), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007966	Leukodystrophy, Metachromatic	C10.228.140.163.100.362.550; C10.228.140.163.100.435.825.850.500; C10.228.140.695.625.550; C10.314.400.550; C16.320.565.189.362.550; C16.320.565.189.435.825.850.500; C16.320.565.398.641.803.925.500; C16.320.565.595.554.825.850.500; C18.452.132.100.362.550; C18.452.132.100.435.825.850.500; C18.452.584.563.641.803.925.500; C18.452.648.189.362.550; C18.452.648.189.435.825.850.500; C18.452.648.398.641.803.925.500; C18.452.648.595.554.825.850.500
C536801	Telomeric 22q13 Monosomy Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5267 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

25 potent at pChembl≥5 of 25 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.20	IC50	0.631	nM	CHEMBL4857810
9.00	IC50	1	nM	CHEMBL4851152
8.80	IC50	1.585	nM	CHEMBL4877585
8.30	IC50	5.012	nM	CHEMBL4850259
8.20	IC50	6.31	nM	CHEMBL4871934
8.10	IC50	7.943	nM	CHEMBL4852669
7.50	IC50	31.62	nM	CHEMBL4879142
7.10	IC50	79.43	nM	CHEMBL4876643
7.00	IC50	100	nM	CHEMBL4856402
7.00	IC50	100	nM	CHEMBL4873687
6.90	IC50	125.9	nM	CHEMBL4861626
6.90	IC50	125.9	nM	CHEMBL4850583
6.70	IC50	199.5	nM	CHEMBL4858139
6.50	IC50	316.2	nM	CHEMBL4866548
6.50	IC50	316.2	nM	CHEMBL4866915
6.30	IC50	501.2	nM	CHEMBL4862324
6.10	IC50	794.3	nM	CHEMBL4853766
6.00	IC50	1000	nM	CHEMBL4851106
6.00	IC50	1000	nM	CHEMBL4878394
6.00	IC50	1000	nM	CHEMBL4874859
5.90	IC50	1259	nM	CHEMBL4864804
5.90	IC50	1259	nM	CHEMBL4874651
5.70	IC50	1995	nM	CHEMBL4865654
5.50	IC50	3162	nM	CHEMBL4846989
5.10	IC50	7943	nM	CHEMBL4870543

PubChem BioAssay actives

25 with measured affinity, of 28 total; 25 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
2,2-dimethyl-N-[[2-(methylaminomethyl)phenyl]methyl]-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0006	uM
N-[[2-[(cyclopropylamino)methyl]phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0010	uM
N-[[2-(azetidin-1-ylmethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0016	uM
N-[[2-(1-aminoethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0050	uM
N-[(2-aminophenyl)methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0063	uM
N-[[2-(aminomethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0079	uM
N-[[2-(2-aminoethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0316	uM
2-[[2,2-dimethylpropanoyl-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]amino]methyl]benzamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.0794	uM
2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]-N-(1,2,3,4-tetrahydroisoquinolin-8-ylmethyl)propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.1000	uM
N-[[2-[(diaminomethylideneamino)methyl]phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.1000	uM
N-[[2-(imidazol-1-ylmethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.1259	uM
N-[[2-(hydroxymethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.1259	uM
N-benzyl-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.1995	uM
2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]-N-[(2-pyrrolidin-3-ylphenyl)methyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.3162	uM
N-(1H-indazol-4-ylmethyl)-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.3162	uM
N-[(2-cyanophenyl)methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.5012	uM
N-[1-[2-(aminomethyl)phenyl]ethyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	0.7943	uM
2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]-N-(pyridin-2-ylmethyl)propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	1.0000	uM
2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]-N-(1,3-thiazol-2-ylmethyl)propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	1.0000	uM
2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]-N-[(2-pyridin-3-ylphenyl)methyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	1.0000	uM
2,2-dimethyl-N-[[2-(morpholin-4-ylmethyl)phenyl]methyl]-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	1.2589	uM
N-benzyl-2,2-dimethyl-N-[2-[(1’-methyl-2’,4’-dioxospiro[1,3-dihydroindene-2,5’-imidazolidine]-5-yl)amino]-2-oxoethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	1.2589	uM
N-[[3-(aminomethyl)-2-pyridinyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	1.9953	uM
N-[[3-(aminomethyl)phenyl]methyl]-2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	3.1623	uM
2,2-dimethyl-N-[2-oxo-2-[(2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl)amino]ethyl]-N-[(2-phenylpyrazol-3-yl)methyl]propanamide	1761959: Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	ic50	7.9433	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
bisphenol A	affects expression, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
GSK-J4	decreases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
enniatins	increases expression	1
3-nitrobenzanthrone	decreases expression	1
ICG 001	increases expression	1
VULM 1457	decreases reaction, increases expression	1
jinfukang	increases expression	1
prothioconazole	increases expression	1
(+)-JQ1 compound	decreases expression	1
NSC668394	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
IWR-1 compound	decreases activity, decreases reaction, decreases expression, decreases phosphorylation, increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Amiodarone	decreases activity, decreases reaction, decreases expression, decreases phosphorylation, increases expression (+1 more)	1
Atrazine	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4820957	Binding	Antagonist activity at human AM2 expressed in 1321N1 cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by forskolin addition in presence of IBMX and measured after 15 mins by TR-FRET assay	Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure-Activity Relationships and Optimization. — J Med Chem

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder