NOS3

Summary

NOS3 (nitric oxide synthase 3, HGNC:7876) is a protein-coding gene on chromosome 7q36.1, encoding Nitric oxide synthase 3 (P29474). Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway.

Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants.

Source: NCBI Gene 4846 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 189 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000603

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7876
Approved symbol	NOS3
Name	nitric oxide synthase 3
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	ECNOS, eNOS
Ensembl gene	ENSG00000164867
Ensembl biotype	protein_coding
OMIM	163729
Entrez	4846

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000297494, ENST00000460603, ENST00000461406, ENST00000467517, ENST00000468293, ENST00000473057, ENST00000475017, ENST00000475454, ENST00000477227, ENST00000484524, ENST00000908206, ENST00000943232, ENST00000943234

RefSeq mRNA: 4 — MANE Select: NM_000603 NM_000603, NM_001160109, NM_001160110, NM_001160111

CCDS: CCDS55182, CCDS55183, CCDS5912

Canonical transcript exons

ENST00000297494 — 27 exons

Exon	Start	End
ENSE00001088117	151009398	151009585
ENSE00001088120	151006427	151006494
ENSE00001088124	151006889	151007005
ENSE00001088128	151007102	151007276
ENSE00001088131	150998539	150998680
ENSE00001088133	151001231	151001425
ENSE00001088137	151010597	151010807
ENSE00001088139	150998946	150999085
ENSE00001088143	151001821	151001965
ENSE00001088144	151010115	151010287
ENSE00001088150	150999190	150999364
ENSE00001088154	151000498	151000599
ENSE00001088158	150996763	150996925
ENSE00001088160	150996404	150996552
ENSE00001088161	151008930	151009062
ENSE00001088163	151001544	151001617
ENSE00001141355	151014008	151014588
ENSE00001141361	150993753	150993961
ENSE00001851539	150991017	150991300
ENSE00003463030	151013724	151013918
ENSE00003463776	151013231	151013379
ENSE00003545944	150995203	150995314
ENSE00003585672	151010899	151010986
ENSE00003622733	151012351	151012472
ENSE00003634102	151009189	151009267
ENSE00003642116	150998357	150998448
ENSE00003648730	151002200	151002304

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 96.16.

FANTOM5 (CAGE): breadth broad, TPM avg 15.3641 / max 479.1941, expressed in 887 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82024	9.6081	412
82027	1.4593	304
82028	1.3921	251
82023	1.0436	320
82030	0.8136	179
82031	0.7703	135
82019	0.0849	23
82022	0.0770	44
82029	0.0425	18
82020	0.0323	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	96.16	gold quality
apex of heart	UBERON:0002098	93.22	gold quality
lower esophagus mucosa	UBERON:0035834	90.66	gold quality
omental fat pad	UBERON:0010414	90.15	gold quality
peritoneum	UBERON:0002358	90.02	gold quality
right atrium auricular region	UBERON:0006631	89.55	gold quality
metanephros cortex	UBERON:0010533	88.23	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.69	gold quality
upper lobe of left lung	UBERON:0008952	87.28	gold quality
left uterine tube	UBERON:0001303	87.12	gold quality
heart left ventricle	UBERON:0002084	86.77	gold quality
body of uterus	UBERON:0009853	86.58	gold quality
cardiac atrium	UBERON:0002081	86.12	gold quality
right lobe of thyroid gland	UBERON:0001119	85.93	gold quality
left coronary artery	UBERON:0001626	85.85	gold quality
right coronary artery	UBERON:0001625	85.84	gold quality
cardiac ventricle	UBERON:0002082	85.67	gold quality
mucosa of stomach	UBERON:0001199	85.65	gold quality
tibial nerve	UBERON:0001323	85.45	gold quality
right lung	UBERON:0002167	85.02	gold quality
left lobe of thyroid gland	UBERON:0001120	84.47	gold quality
heart	UBERON:0000948	83.88	gold quality
upper lobe of lung	UBERON:0008948	83.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.41	gold quality
coronary artery	UBERON:0001621	83.39	gold quality
adenohypophysis	UBERON:0002196	83.38	gold quality
left testis	UBERON:0004533	83.33	gold quality
ectocervix	UBERON:0012249	83.21	gold quality
sural nerve	UBERON:0015488	83.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting NOS3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-4448	97.04	66.22	752

Literature-anchored findings (GeneRIF, showing 40)

• data fall short of showing significant association between a variant of the promoter of interleukin-1beta, polymorphism of angiotensinogen, and the missense variant of endothelial nitric oxide synthase and occurrence of idiopathic recurrent miscarriage (PMID:11756575)
• Glu298Asp polymorphism is associated with a 5 year lower mean age at end stage renal disease in males with AD polycytic kidneys. (PMID:11823442)
• Endothelial nitric oxide gene polymorphism (Glu298Asp) is not associated with coronary artery disease in Turkish population. (PMID:11858501)
• The human alveolar type II epithelium-like cell line A549 expresses nitric oxide synthase type 2 (NOS2), but not NOS3. (PMID:11880293)
• Effect of ecNOS polymorphisms and coronary artery disease upon exhaled nitric oxide (PMID:11894144)
• Association of a polymorphism of the ecNOS gene with myocardial infarction in a subgroup of Turkish MI patients (PMID:11903359)
• Play a key role in regulation of airway function and in the pathophysiology of inflammation in IgE-mediated allergic disease. (PMID:11906374)
• Endothelial nitric oxide synthase gene polymorphisms in Behcet’s disease. (PMID:11908569)
• Polymorphism of the endothelial nitric oxide synthase predicts risk for severe diabetic retinopathy. (enos4) (PMID:11918626)
• the role and intracellular signal pathway of endothelial nitric oxide synthase (eNOS) activation induced by VEGF (PMID:11961297)
• Increased risk of systemic sclerosis in eNOS 894T allele carriers. (PMID:12015245)
• Data provides evidence for association between preeclampsia and a polymorphism of the NOS3 gene. (PMID:12044319)
• Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells. (PMID:12060567)
• Glu298Asp polymorphism is associated with differences in endothelial responses to both smoking and n-3 fatty acids in healthy young subjects, and these findings raise the possibility of genotype-specific prevention strategies in cardiovascular disease. (PMID:12065317)
• the a allele of the ecNOS gene polymorphism showed a significantly higher incidence among patients with end-stage renal failure caused by autosomal dominant polycystic kidney disease (PMID:12077489)
• in addition to alpha-gal A gene mutations, eNOS genetic variations are implicated in Fabry’s disease (PMID:12121349)
• ecNOS gene polymorphism is associated with endothelium-dependent vasodilation in Type 2 diabetes. (PMID:12124201)
• effects of gene polymorphisms on platelet function, nitric oxide release, and interactions with estradiol (PMID:12142730)
• Polymorphisms of the eNOS gene were significantly associated with high-altitude pulmonary edema (PMID:12176955)
• association of not-GG genotype with a-allele from ecNOS4a/b polymorphism is related to significant increase in susceptibility to prostate cancer (PMID:12195160)
• Smoking status-dependent association of the 27-bp repeat polymorphism in intron 4 of endothelial nitric oxide synthase gene with plasma nitric oxide concentrations. (PMID:12204432)
• This gene 4a/b polymorphism was not associated with the extent of coronary arteriosclerosis, but the a-allele of the variant seems to protect to some degree against the development of myocardial infarction. (PMID:12226742)
• human enos binds to porin, a voltage-dependent anion channel (PMID:12228731)
• C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells (PMID:12234944)
• The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension. (PMID:12359981)
• assessment of association of human endothelial nitric oxide synthase gene polymorphism with the myocardial infarction (PMID:12362496)
• conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis (PMID:12364322)
• Association of eNOS Glu298Asp polymorphism with end-stage renal disease (PMID:12364359)
• in patients with endometriosis a significant negative correlation was observed between luminal expression of eNOS and alpha(v)beta(3) integrin and between glandular expression of eNOS and luminal expression of alpha(v)beta(3) integrin (PMID:12372469)
• activity decreases during type I collagen-induced platelet aggregation and may be controlled with differential phosphorylation of specific amino acid residues located in the enzyme (PMID:12379480)
• While eNOS seems to be involved in the physiological regulation of hepatic perfusion in fulminant hepatic failure (PMID:12399227)
• Polymorphism of this gene is not related to the development of diabetic nephropathy. (PMID:12413777)
• Association analysis of five polymorphic microsatellite markers in cluster headache (CH) patients reveals that genetic variations in NOS3 do not contribute greatly to CH susceptibility. (PMID:12421162)
• regression analyses indicate no substantial effect of G894T polymorphism on the variance of plasma NO(x) levels in healthy Korean population (PMID:12431478)
• The (-)786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients (PMID:12436344)
• nitric oxide synthases(inducible, brain and endothelial) were expressed in human pregnant term uterus and did not change in the myometrium during labor (PMID:12445599)
• we have identified a nitric oxide related genetic factor associated with micrometastization of prostate cancer (PMID:12445681)
• data demonstrate that Rho/ROCK pathway negatively regulates eNOS phosphorylation through inhibition of protein kinase B (PKB), whereas it downregulates eNOS expression independent of PKB. (PMID:12446767)
• The G894T mutation of the endothelial nitric oxide synthase gene may be a marker for genetical predisposition of CHD in Chinese Han population. (PMID:12476417)
• Tandem repeat polymorphism in intron 4 of Nos3 was analyzed by polymerase chain reaction. The common B allele was identified on 143 of 182 chromosomes (frequency 0.79). The polymorphic A allele was present on 39 chromosomes (frequency 0.21). (PMID:12477509)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nos3	ENSMUSG00000028978
rattus_norvegicus	Nos3	ENSRNOG00000009348

Paralogs (5): NOS2 (ENSG00000007171), NOS1 (ENSG00000089250), MTRR (ENSG00000124275), POR (ENSG00000127948), NDOR1 (ENSG00000188566)

Protein

Protein identifiers

Nitric oxide synthase 3 — P29474 (reviewed: P29474)

Alternative names: Constitutive NOS, EC-NOS, NOS type III, Nitric oxide synthase, endothelial

All UniProt accessions (3): E7ESA7, P29474, H7C4V4

UniProt curated annotations — full annotation on UniProt →

Function. Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.

Subunit / interactions. Homodimer. Interacts with NOSIP and NOSTRIN. Interacts with HSP90AB1. Forms a complex with ASL, ASS1 and SLC7A1; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.

Subcellular location. Cell membrane. Membrane. Caveola. Cytoplasm. Cytoskeleton. Golgi apparatus.

Tissue specificity. Platelets, placenta, liver and kidney.

Post-translational modifications. Phosphorylation by AMPK at Ser-1177 in the presence of Ca(2+)-calmodulin (CaM) activates activity. In absence of Ca(2+)-calmodulin, AMPK also phosphorylates Thr-495, resulting in inhibition of activity. Phosphorylation of Ser-114 by CDK5 reduces activity.

Disease relevance. Variation Asp-298 in NOS3 may be associated with susceptibility to coronary spasm.

Activity regulation. Stimulated by calcium/calmodulin. Inhibited by NOSIP and NOSTRIN.

Cofactor. Binds 1 FAD. Binds 1 FMN. Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.

Miscellaneous. Lacks eNOS activity.

Similarity. Belongs to the NOS family.

Isoforms (3)

UniProt ID	Names	Canonical?
P29474-1	1	yes
P29474-2	eNOS13C
P29474-3	eNOS13B

RefSeq proteins (4): NP_000594, NP_001153581, NP_001153582, NP_001153583 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001094	Flavdoxin-like	Domain
IPR001433	OxRdtase_FAD/NAD-bd	Domain
IPR001709	Flavoprot_Pyr_Nucl_cyt_Rdtase	Domain
IPR003097	CysJ-like_FAD-binding	Domain
IPR004030	NOS_N	Domain
IPR008254	Flavodoxin/NO_synth	Domain
IPR012144	NOS_euk	Family
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR023173	NADPH_Cyt_P450_Rdtase_alpha	Homologous_superfamily
IPR029039	Flavoprotein-like_sf	Homologous_superfamily
IPR036119	NOS_N_sf	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily
IPR044940	NOS_dom_2	Homologous_superfamily
IPR044943	NOS_dom_1	Homologous_superfamily
IPR044944	NOS_dom_3	Homologous_superfamily
IPR050607	NOS	Family

Pfam: PF00175, PF00258, PF00667, PF02898

Enzyme classification (BRENDA):

• EC 1.14.13.39 — nitric-oxide synthase (NADPH) (BRENDA: 31 organisms, 140 substrates, 179 inhibitors, 88 Km, 25 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-ARGININE	0.0019–68.5	28
NADPH	0.0003–0.0041	9
TETRAHYDROBIOPTERIN	—	6
ADRIAMYCIN	0.012–0.078	5
MENADIONE	0.01–0.041	5
MITOMYCIN C	0.0073–0.055	5
NGAMMA-HYDROXY-L-ARGININE	0.019–0.129	5
2’,3’-DIALDEHYDE-NADPH	0.0008	1
CALMODULIN	—	1
NITROBLUE TETRAZOLIUM	0.016	1
NITRIC OXIDE	—	0

Catalyzed reactions (Rhea), 1 shown:

• 2 L-arginine + 3 NADPH + 4 O2 + H(+) = 2 L-citrulline + 2 nitric oxide + 3 NADP(+) + 4 H2O (RHEA:19897)

UniProt features (131 total): binding site 42, strand 23, helix 22, modified residue 10, sequence variant 8, sequence conflict 7, splice variant 4, region of interest 3, lipid moiety-binding region 3, turn 2, domain 2, compositionally biased region 2, initiator methionine 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

105 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9CWI	X-RAY DIFFRACTION	1.73
4D1P	X-RAY DIFFRACTION	1.73
9MWU	X-RAY DIFFRACTION	1.74
6PP1	X-RAY DIFFRACTION	1.76
9MWO	X-RAY DIFFRACTION	1.76
8UFT	X-RAY DIFFRACTION	1.78
8FGO	X-RAY DIFFRACTION	1.8
6NH8	X-RAY DIFFRACTION	1.8
9MWW	X-RAY DIFFRACTION	1.8
9Q51	X-RAY DIFFRACTION	1.8
4D1O	X-RAY DIFFRACTION	1.82
6NHF	X-RAY DIFFRACTION	1.83
9CW7	X-RAY DIFFRACTION	1.83
9MWX	X-RAY DIFFRACTION	1.84
8FGS	X-RAY DIFFRACTION	1.84
7TSG	X-RAY DIFFRACTION	1.85
7TSM	X-RAY DIFFRACTION	1.85
9MWP	X-RAY DIFFRACTION	1.86
8UFR	X-RAY DIFFRACTION	1.87
8FGP	X-RAY DIFFRACTION	1.88
9CW5	X-RAY DIFFRACTION	1.88
9Q53	X-RAY DIFFRACTION	1.88
9MWV	X-RAY DIFFRACTION	1.9
9MWS	X-RAY DIFFRACTION	1.9
6NH7	X-RAY DIFFRACTION	1.9
7TSL	X-RAY DIFFRACTION	1.9
7UAO	X-RAY DIFFRACTION	1.9
8FGT	X-RAY DIFFRACTION	1.9
9CWJ	X-RAY DIFFRACTION	1.9
9CWK	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29474-F1	83.20	0.56

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 (42): 99; 102; 184 (axial binding residue); 247; 356; 357; 361; 365; 366; 446; 447; 460 …

Post-translational modifications (13): 33, 114, 495, 615, 633, 638, 836, 1175, 1177, 1179, 2, 15, 26

Mutagenesis-validated functional residues (1):

Position	Phenotype
114	reduced nitrite (no) production.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
R-HSA-203615	eNOS activation
R-HSA-203641	NOSTRIN mediated eNOS trafficking
R-HSA-203754	NOSIP mediated eNOS trafficking
R-HSA-392154	Nitric oxide stimulates guanylate cyclase
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 446 (showing top): PID_SHP2_PATHWAY, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POTASSIUM_ION_TRANSPORT, BIOCARTA_GCR_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN

GO Biological Process (51): angiogenesis (GO:0001525), ovulation from ovarian follicle (GO:0001542), in utero embryonic development (GO:0001701), blood vessel remodeling (GO:0001974), regulation of sodium ion transport (GO:0002028), regulation of the force of heart contraction by chemical signal (GO:0003057), regulation of systemic arterial blood pressure by endothelin (GO:0003100), aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), endocardial cushion morphogenesis (GO:0003203), L-arginine catabolic process (GO:0006527), protein import into nucleus (GO:0006606), nitric oxide biosynthetic process (GO:0006809), potassium ion transport (GO:0006813), calcium ion transport (GO:0006816), mitochondrion organization (GO:0007005), obsolete nitric oxide mediated signal transduction (GO:0007263), regulation of blood pressure (GO:0008217), negative regulation of cell population proliferation (GO:0008285), response to heat (GO:0009408), response to hormone (GO:0009725), gene expression (GO:0010467), negative regulation of platelet activation (GO:0010544), positive regulation of gene expression (GO:0010628), negative regulation of muscle hyperplasia (GO:0014740), smooth muscle hyperplasia (GO:0014806), removal of superoxide radicals (GO:0019430), lung development (GO:0030324), regulation of nervous system process (GO:0031644), lipopolysaccharide-mediated signaling pathway (GO:0031663), response to lipopolysaccharide (GO:0032496), response to fluid shear stress (GO:0034405), vasodilation (GO:0042311), negative regulation of potassium ion transport (GO:0043267), positive regulation of blood vessel endothelial cell migration (GO:0043536), endothelial cell migration (GO:0043542), cell redox homeostasis (GO:0045454), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of angiogenesis (GO:0045766), negative regulation of blood pressure (GO:0045776)

GO Molecular Function (15): actin monomer binding (GO:0003785), nitric-oxide synthase activity (GO:0004517), calmodulin binding (GO:0005516), FMN binding (GO:0010181), superoxide-generating NAD(P)H oxidase activity (GO:0016175), heme binding (GO:0020037), tetrahydrobiopterin binding (GO:0034617), arginine binding (GO:0034618), cadmium ion binding (GO:0046870), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), scaffold protein binding (GO:0097110), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (10): Golgi membrane (GO:0000139), nucleus (GO:0005634), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), caveola (GO:0005901), endocytic vesicle membrane (GO:0030666), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Metabolism of nitric oxide: NOS3 activation and regulation	3
Innate Immune System	1
Metabolism of cofactors	1
Platelet homeostasis	1
VEGFA-VEGFR2 Pathway	1
ESR-mediated signaling	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
heart valve morphogenesis	2
metal ion transport	2
protein binding	2
anion binding	2
binding	2
cation binding	2
bounding membrane of organelle	2
intracellular membrane-bounded organelle	2
cytoplasm	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
female gonad development	1
ovulation cycle process	1
ovulation	1
chordate embryonic development	1
tissue remodeling	1
sodium ion transport	1
regulation of metal ion transport	1
regulation of the force of heart contraction	1
regulation of systemic arterial blood pressure by hormone	1
aortic valve development	1
pulmonary valve development	1
heart morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
arginine metabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
biosynthetic process	1
nitric oxide metabolic process	1
organelle organization	1
blood circulation	1
regulation of biological quality	1
cell population proliferation	1
regulation of cell population proliferation	1

Protein interactions and networks

STRING

3276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOS3	CALM1	P02593	996
NOS3	CALML3	P27482	996
NOS3	CALML6	Q8TD86	996
NOS3	CALML4	Q96GE6	996
NOS3	CALML5	Q9NZT1	996
NOS3	CAV1	Q03135	995
NOS3	HSP90AA1	P07900	992
NOS3	HSP90AB1	P08238	992
NOS3	NOSIP	Q9Y314	961
NOS3	AKT1	P31749	909
NOS3	EDN1	P05305	884
NOS3	DDAH1	O94760	865
NOS3	ACTB	P02570	853
NOS3	XDH	P47989	828
NOS3	KNG1	P01042	823

IntAct

222 interactions, top by confidence:

A	B	Type	Score
ESR1	SRC	psi-mi:“MI:0914”(association)	0.850
NOS3	NOSTRIN	psi-mi:“MI:0915”(physical association)	0.730
NOSTRIN	NOS3	psi-mi:“MI:0915”(physical association)	0.730
NOSTRIN	NOS3	psi-mi:“MI:0403”(colocalization)	0.730
GOLGA2	NOS3	psi-mi:“MI:0915”(physical association)	0.720
NOS3	GOLGA2	psi-mi:“MI:0915”(physical association)	0.720
CDC37	NOS3	psi-mi:“MI:0407”(direct interaction)	0.580
CDC37	NOS3	psi-mi:“MI:0914”(association)	0.580
CDC37	NOS3	psi-mi:“MI:0915”(physical association)	0.580
NOS3	MAGEA11	psi-mi:“MI:0915”(physical association)	0.560
MAGEA11	NOS3	psi-mi:“MI:0915”(physical association)	0.560
NOS3	IKZF3	psi-mi:“MI:0915”(physical association)	0.560
NOS3	AP2B1	psi-mi:“MI:0915”(physical association)	0.560
NOS3	FANCG	psi-mi:“MI:0915”(physical association)	0.560
NOS3	HNRNPK	psi-mi:“MI:0915”(physical association)	0.560
NOS3	KRT33B	psi-mi:“MI:0915”(physical association)	0.560
NOS3	NVL	psi-mi:“MI:0915”(physical association)	0.560
NOS3	PDZK1	psi-mi:“MI:0915”(physical association)	0.560
NOS3	ZNF232	psi-mi:“MI:0915”(physical association)	0.560
NOS3	COPS3	psi-mi:“MI:0915”(physical association)	0.560
NOS3	PIAS1	psi-mi:“MI:0915”(physical association)	0.560
NOS3	HYAL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (108): NOS3 (Biochemical Activity), NOS3 (Two-hybrid), NOS3 (Two-hybrid), NOS3 (Affinity Capture-Western), NOS3 (Co-localization), PPP2R4 (Affinity Capture-Western), PPP2R4 (Co-localization), NOS3 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), NOS3 (Reconstituted Complex), NOS3 (Affinity Capture-Western), GUCY1B3 (Affinity Capture-Western), NOS3 (Reconstituted Complex), NOS3 (Two-hybrid), CALM1 (Reconstituted Complex)

ESM2 similar proteins: A0A1W2PP97, A6NLX4, A6QNY1, P0DJK0, P12838, P13207, P22389, P22749, P23943, P29473, P29474, P55056, P70313, P79209, P97270, P98162, Q1RMT9, Q28969, Q2TAL6, Q2VPJ9, Q4TUC0, Q566C8, Q5BIR3, Q5JTB6, Q5NRP8, Q5RCS3, Q5SPX3, Q5XIX0, Q62600, Q64322, Q7TMJ8, Q7TPD7, Q7TSF4, Q80TT8, Q867D0, Q8BZT7, Q8C8N3, Q8K1T4, Q8K4Z2, Q8MJW9

Diamond homologs: A0A2U1KZS6, A0A2U1LIM9, A0A7T9QPQ1, A0KTH4, A1AEV0, A2QS05, A5F3I4, A6TD49, A7MJ63, A7ZQK7, A8A3P5, A8ANX1, A8G9X6, A9LZ73, A9MF16, B1IU77, C5YJG8, O08336, O08394, O19114, O19132, O32214, O54705, O62699, P00388, P00389, P04175, P14779, P16435, P16603, P19618, P29474, P29475, P29476, P29477, P35228, P36587, P37039, P37040, P37116

SIGNOR signaling

45 interactions.

A	Effect	B	Mechanism
AKT1	up-regulates	NOS3	phosphorylation
PRKAB1	up-regulates	NOS3	phosphorylation
PRKACA	up-regulates	NOS3	phosphorylation
PRKACG	up-regulates	NOS3	phosphorylation
PRKAA1	up-regulates	NOS3	phosphorylation
PTK2B	down-regulates	NOS3	phosphorylation
CDK5	down-regulates	NOS3	phosphorylation
AMPK	up-regulates	NOS3	phosphorylation
AKT	up-regulates	NOS3	phosphorylation
PPP1CC	“up-regulates activity”	NOS3	dephosphorylation
PPP1CA	“up-regulates activity”	NOS3	dephosphorylation
PPP1CB	“up-regulates activity”	NOS3	dephosphorylation
CALM1	“up-regulates activity”	NOS3	binding
PRKACA	“up-regulates activity”	NOS3	phosphorylation
AMPK	“down-regulates activity”	NOS3	phosphorylation
PRKAA1	“up-regulates activity”	NOS3	phosphorylation
PRKCA	“down-regulates activity”	NOS3	phosphorylation
AKT1	“up-regulates activity”	NOS3	phosphorylation
AKT2	“up-regulates activity”	NOS3	phosphorylation
AKT3	“up-regulates activity”	NOS3	phosphorylation
AKT	“up-regulates activity”	NOS3	phosphorylation
NOS3	“up-regulates quantity”	“nitric oxide”	“chemical modification”
PRKCB	“down-regulates activity”	NOS3	phosphorylation
PRKCD	“down-regulates activity”	NOS3	phosphorylation
PRKCE	“down-regulates activity”	NOS3	phosphorylation
PRKCG	“down-regulates activity”	NOS3	phosphorylation
PRKCH	“down-regulates activity”	NOS3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oncogenic MAPK signaling	6	28.1×	4e-05
MAPK1/MAPK3 signaling	6	14.9×	7e-04
MAPK family signaling cascades	6	11.7×	1e-03
Platelet activation, signaling and aggregation	5	10.0×	1e-02
Diseases of signal transduction by growth factor receptors and second messengers	8	8.6×	7e-04
Signaling by Receptor Tyrosine Kinases	8	7.8×	1e-03
RAF/MAP kinase cascade	6	6.9×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	109
Likely benign	27
Benign	34

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
4686577	NOS3, IVS12, G-C, +1	Pathogenic
4686578	C648R	Pathogenic
929757	NM_000603.5(NOS3):c.172C>T (p.Pro58Ser)	Likely pathogenic
929758	NM_000603.5(NOS3):c.505G>A (p.Glu169Lys)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

7770 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:150996875:T:A	W178R	1.000
7:150996875:T:C	W178R	1.000
7:151007103:T:C	F647L	1.000
7:151007105:C:A	F647L	1.000
7:151007105:C:G	F647L	1.000
7:151014035:T:C	F1160L	1.000
7:151014037:C:A	F1160L	1.000
7:151014037:C:G	F1160L	1.000
7:150996533:T:G	Y134D	0.999
7:150996861:G:A	G173E	0.999
7:150996877:G:C	W178C	0.999
7:150996877:G:T	W178C	0.999
7:150996878:C:A	R179S	0.999
7:150996879:G:C	R179P	0.999
7:150996893:T:C	C184R	0.999
7:150996903:G:C	R187P	0.999
7:150996911:T:A	W190R	0.999
7:150996911:T:C	W190R	0.999
7:150996913:G:C	W190C	0.999
7:150996913:G:T	W190C	0.999
7:150996921:T:C	L193P	0.999
7:150998550:C:A	T229K	0.999
7:150998599:C:A	N245K	0.999
7:150998599:C:G	N245K	0.999
7:150999293:A:C	S354R	0.999
7:150999295:T:A	S354R	0.999
7:150999295:T:G	S354R	0.999
7:150999299:T:A	W356R	0.999
7:150999299:T:C	W356R	0.999
7:151001277:T:C	F427S	0.999

dbSNP variants (sampled 300 via entrez): RS1000071234 (7:150994739 T>C), RS1000101951 (7:150989118 T>A,C,G), RS1000125509 (7:150994043 T>A,C), RS1000177356 (7:150995566 T>C,G), RS1000318386 (7:151004860 G>T), RS1000362669 (7:151013486 G>A,C,T), RS1000491396 (7:151010657 G>A), RS1000880377 (7:151012987 G>A,T), RS1000960483 (7:150994920 C>T), RS1001099345 (7:151011955 G>A,C), RS1001275654 (7:150993707 C>A,G,T), RS1001492945 (7:151009086 C>A,G), RS1001588659 (7:151006073 G>A), RS1001717812 (7:150997830 C>T), RS1001748820 (7:150998061 T>C)

Disease associations

OMIM: gene MIM:163729 | disease phenotypes: MIM:104300, MIM:145500, MIM:189800, MIM:621469

GenCC curated gene-disease

Mondo (8): Alzheimer disease (MONDO:0004975), Alzheimer disease type 1 (MONDO:0007088), essential hypertension, genetic (MONDO:0007781), preeclampsia/eclampsia 1 (MONDO:0100467), ischemic stroke (MONDO:1060198), Moyamoya disease 8 (MONDO:0980949), primary ovarian failure (MONDO:0005387), essential hypertension (MONDO:0001134)

Orphanet (4): Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619), NON RARE IN EUROPE: Essential hypertension (Orphanet:243761)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000343	Long philtrum
HP:0000501	Glaucoma
HP:0000545	Myopia
HP:0000750	Delayed speech and language development
HP:0000822	Hypertension
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001511	Intrauterine growth retardation
HP:0001998	Neonatal hypoglycemia
HP:0002000	Short columella
HP:0002140	Ischemic stroke
HP:0002326	Transient ischemic attack
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0007301	Oromotor apraxia
HP:0007906	Ocular hypertension
HP:0011834	Moyamoya phenomenon
HP:0012377	Hemianopia
HP:0012493	Middle cerebral artery stenosis
HP:0012494	Anterior cerebral artery stenosis
HP:0012495	Posterior cerebral artery stenosis
HP:0030880	Raynaud phenomenon
HP:0033832	Livedo
HP:0034198	Second trimester onset
HP:0100545	Arterial stenosis

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D000075222	Essential Hypertension	C14.907.489.165
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C536594	Alzheimer disease type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2111350 (SELECTIVITY GROUP), CHEMBL2111405 (SELECTIVITY GROUP), CHEMBL4630725 (PROTEIN FAMILY), CHEMBL4803 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 47,829 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1371	CHLORZOXAZONE	4	16,752
CHEMBL256147	TILARGININE	3	2,020
CHEMBL114551	GW-274150	2	1,052
CHEMBL225304	PIMAGEDINE	2	24,450
CHEMBL7890	L-NAME	2	1,152
CHEMBL227744	NITROARGININE	1	2,403

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Nitric oxide synthases

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

Ligand	Action	Affinity	Parameter
L-NNA	Inhibition	7.52	pKi
tilarginine	Inhibition	6.4	pKi
GW274150	Inhibition	4.47	pIC50

Binding affinities (BindingDB)

86 measured of 136 human assays (174 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[[(2R,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	10 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[3-(dimethylamino)propyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	14 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
N1-((3R,4S)-4-((6-aminopyridin-2-yl)methyl)pyrrolidin-3-yl)-N2-(4-fluorobenzyl)ethane-1,2-diamine tetrahydrochloride	KI	17.7 nM	US-9090589: Specific nNOS inhibitors for the therapy and prevention of human melanoma
4-Methyl-6-propyl-pyridin-2-ylamine	IC50	23 nM
6-[2-[5-[(2R)-1-amino-3-(6-amino-4-methyl-2-pyridinyl)propan-2-yl]-3-pyridinyl]ethyl]-4-methylpyridin-2-amine	KI	24 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N1-{(+/-)-4’-[(6’’-amino-4’’-methylpyridin-2’’-yl)methyl]pyrrolidin-3’-yl}-N2-phenethylethane-1,2-diamine tetrahydrochloride	KI	24 nM	US-9090589: Specific nNOS inhibitors for the therapy and prevention of human melanoma
6-[[(2S,4R)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	26 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[3-(methylamino)propyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	28 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[2-[5-[1-amino-3-(6-amino-4-methyl-2-pyridinyl)propan-2-yl]-3-pyridinyl]ethyl]-4-methylpyridin-2-amine	KI	30 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
6-[[(2S,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	31 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
6-[[(2R)-3-amino-2-[(6-amino-4-methyl-2-pyridinyl)methoxy]propoxy]methyl]-4-methylpyridin-2-amine	KI	32 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[2-(2-hydroxyethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	34 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[[(2R,4R)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxymethyl]-4-methylpyridin-2-amine	KI	34 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
6-[[(2S,3S)-2-amino-3-[(6-amino-4-methyl-2-pyridinyl)methoxy]butoxy]methyl]-4-methylpyridin-2-amine	KI	37 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
NOS Inhibitor, 3h	KI	38 nM
6-[[3-[[2-(3-fluorophenyl)ethylamino]methyl]phenoxy]methyl]-4-methylpyridin-2-amine	KI	40 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
6-[[(2R,3R)-2-amino-3-[(6-amino-4-methyl-2-pyridinyl)methoxy]butoxy]methyl]-4-methylpyridin-2-amine	KI	47 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[2-(ethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-6-yl]thiophene-2-carboximidamide	IC50	50 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[2-[3-[1-amino-3-(6-amino-4-methyl-2-pyridinyl)propan-2-yl]phenyl]ethyl]-4-methylpyridin-2-amine	KI	53 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
3-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-5-[methyl-[2-(methylamino)ethyl]amino]benzonitrile	KI	55 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N’-[3-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]phenyl]-N’-methylethane-1,2-diamine	KI	56 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N’-[4-[2-(methylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	60 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[[3-(3-aminopropoxy)phenoxy]methyl]-4-methylpyridin-2-amine	KI	60 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
2-(6-amino-4-methyl-2-pyridinyl)-1-[3-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]phenyl]ethanol	KI	70 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
6-[2-[5-[(2S)-1-amino-3-(6-amino-4-methyl-2-pyridinyl)propan-2-yl]-3-pyridinyl]ethyl]-4-methylpyridin-2-amine	KI	70 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
6-[2-[[(2S,4R)-4-[(6-amino-4-methyl-2-pyridinyl)methoxy]pyrrolidin-2-yl]methoxy]ethoxymethyl]-4-methylpyridin-2-amine	KI	70 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[2-(methylamino)ethyl]-2,3-dihydro-1,4-benzoxazin-6-yl]thiophene-2-carboximidamide	IC50	80 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
N’-[4-[2-(methylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-6-yl]thiophene-2-carboximidamide	IC50	80 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6,6’-[(5-aminobenzene-1,3-diyl)diethane-2,1-diyl]bis(4-methylpyridin-2-amine)	KI	85 nM
N1-{(+/-)-4’-[(6’’-amino-4’’-methylpyridin-2’’-yl)methyl]pyrrolidin-3’-yl}ethane-1,2-diamine tetrahydrochloride	KI	98 nM	US-9090589: Specific nNOS inhibitors for the therapy and prevention of human melanoma
6,6’-(pyridine-2,6-diyldiethane-2,1-diyl)bis(4-methylpyridin-2-amine)	KI	99 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N’-[3-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-5-fluorophenyl]-N,N’-dimethylethane-1,2-diamine	KI	105 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N’-[3-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]phenyl]-N’-methylpropane-1,3-diamine	KI	109 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N’-(4-piperidin-4-yl-2,3-dihydro-1,4-benzothiazin-6-yl)thiophene-2-carboximidamide	IC50	110 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
N-[3-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]phenyl]-N’,N’-dimethylethane-1,2-diamine	KI	111 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
4-methyl-6-[[3-(piperidin-4-ylmethoxy)phenoxy]methyl]pyridin-2-amine	KI	117 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
N’-[4-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	120 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[2-[6-[1-amino-3-(6-amino-4-methyl-2-pyridinyl)propan-2-yl]-2-pyridinyl]ethyl]-4-methylpyridin-2-amine	KI	123 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
3-(3-chlorophenyl)-N-[2-(2-imidazol-1-ylpyrimidin-4-yl)ethyl]propan-1-amine	KI	125 nM	US-9878996: 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
N-[2-(2-imidazol-1-ylpyrimidin-4-yl)ethyl]-3-pyridin-3-ylpropan-1-amine	KI	125 nM	US-9878996: 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
N’-[4-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-6-yl]thiophene-2-carboximidamide	IC50	130 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
2-(2-imidazol-1-ylpyrimidin-4-yl)-N-[(3-isocyanophenyl)methyl]ethanamine	KI	138 nM	US-9878996: 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
N’-[4-(2-piperidin-1-ylethyl)-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	140 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
N’-[4-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-7-yl]furan-2-carboximidamide	IC50	140 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
N’-[4-(3-pyrrolidin-1-ylpropyl)-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	140 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[[5-[[2-(3-fluorophenyl)ethylamino]methyl]-3-pyridinyl]oxymethyl]-4-methylpyridin-2-amine	KI	140 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors
6-[2-[3-[(1S)-1-amino-2-(6-amino-4-methyl-2-pyridinyl)ethyl]phenyl]ethyl]-4-methylpyridin-2-amine	KI	144 nM	US-9951014: Mammalian and bacterial nitric oxide synthase inhibitors
N’-[4-[2-(diethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-7-yl]thiophene-2-carboximidamide	IC50	150 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
N’-[4-[2-(2-hydroxyethylamino)ethyl]-2,3-dihydro-1,4-benzothiazin-6-yl]thiophene-2-carboximidamide	IC50	150 nM	US-8618286: Benzoxazines, benzothiazines, and related compounds having NOS inhibitory activity
6-[[(3R,5S)-5-[2-[(3-fluorophenyl)methoxy]ethoxymethyl]pyrrolidin-3-yl]oxymethyl]-4-methylpyridin-2-amine	KI	153 nM	US-9732037: 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors

ChEMBL bioactivities

435 potent at pChembl≥5 of 966 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.75	Ki	18	nM	CHEMBL105792
7.73	Ki	18.62	nM	CHEMBL1800346
7.66	Ki	22	nM	CHEMBL483091
7.62	Ki	24	nM	CHEMBL106871
7.52	Ki	30	nM	NITROARGININE
7.47	IC50	34	nM	CHEMBL302657
7.41	Ki	39	nM	ETHYLISOTHIOUREA
7.35	IC50	45	nM	CHEMBL59925
7.35	IC50	44.67	nM	CHEMBL59925
7.31	IC50	49	nM	CHEMBL294084
7.30	IC50	50	nM	CHEMBL8365
7.30	IC50	50	nM	CHEMBL302657
7.14	IC50	72	nM	CHEMBL40833
7.10	Ki	80	nM	CHEMBL227937
7.10	IC50	80	nM	CHEMBL1221702
7.10	IC50	80	nM	CHEMBL8292
7.09	IC50	81	nM	CHEMBL61427
7.07	Ki	85.2	nM	CHEMBL474637
7.02	Ki	95.2	nM	CHEMBL526688
7.00	IC50	100	nM	CHEMBL40833
6.97	Ki	107	nM	CHEMBL44833
6.96	Ki	110	nM	CHEMBL228077
6.92	IC50	120	nM	CHEMBL8281
6.84	IC50	146	nM	CHEMBL6808
6.82	IC50	150	nM	CHEMBL294609
6.82	IC50	150	nM	CHEMBL61939
6.80	IC50	160	nM	CHEMBL7945
6.77	IC50	170	nM	CHEMBL59925
6.75	IC50	180	nM	CHEMBL272708
6.75	IC50	180	nM	CHEMBL354788
6.70	IC50	200	nM	CHEMBL1230023
6.70	IC50	200	nM	CHEMBL299677
6.70	IC50	200	nM	CHEMBL1221703
6.66	IC50	220	nM	CHEMBL428069
6.66	IC50	220	nM	CHEMBL6808
6.64	IC50	230	nM	CHEMBL62077
6.64	IC50	230	nM	CHEMBL75304
6.62	IC50	240	nM	CHEMBL74919
6.60	Ki	250	nM	CHEMBL298404
6.60	IC50	250	nM	CHEMBL1783094
6.57	Ki	270	nM	CHEMBL49881
6.55	IC50	280	nM	CHEMBL268521
6.52	IC50	300	nM	TILARGININE
6.52	IC50	300	nM	CHEMBL40833
6.52	IC50	300	nM	CHEMBL269076
6.50	IC50	320	nM	NITROARGININE
6.50	IC50	320	nM	CHEMBL40833
6.50	IC50	320	nM	CHEMBL75484
6.50	Ki	320	nM	CHEMBL555794
6.48	IC50	330	nM	TILARGININE

PubChem BioAssay actives

393 with measured affinity, of 1382 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
(1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-amine	2007174: Inhibition of human eNOS overexpressed in baculovirus infected Sf21 cells assessed as inhibition constant	ki	0.0180	uM
(1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-amine;hydrochloride	607321: Inhibition of human eNOS assessed as inhibition of [3H]L-arginine to [3H]L-citrulline conversion by scintillation counting	ki	0.0186	uM
propan-2-yl carbamimidothioate	2007166: Inhibition of eNOS in human DLD-1 cells assessed as reduction of L-[14C]arginine to L-[14C]citrulline conversion	ki	0.0220	uM
(2S)-2-amino-5-[[amino(ethylsulfanyl)methylidene]amino]pentanoic acid	2007149: Inhibition of human eNOS assessed as inhibition constant	ki	0.0240	uM
(2S)-2-amino-5-[[amino(nitramido)methylidene]amino]pentanoic acid	68156: Inhibitory activity against human endothelial nitric oxide synthase (eNOS) isoenzyme.	ki	0.0300	uM
4-methyl-6-propylpyridin-2-amine	1799391: NOS Enzyme Inhibition Assay from Article 10.1038/nchembio.115: “Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.”	ic50	0.0340	uM
ethyl carbamimidothioate	2007166: Inhibition of eNOS in human DLD-1 cells assessed as reduction of L-[14C]arginine to L-[14C]citrulline conversion	ki	0.0390	uM
4,6-dimethylpyridin-2-amine	607321: Inhibition of human eNOS assessed as inhibition of [3H]L-arginine to [3H]L-citrulline conversion by scintillation counting	ic50	0.0447	uM
6-ethyl-4-methylpyridin-2-amine	68131: Inhibitory activity against endothelial nitric oxide synthase (eNOS)	ic50	0.0490	uM
5-cyclopropyl-4,5-dihydrothieno[2,3-c]pyridin-7-amine	85462: Ability to inhibit the conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by e-NOS from HUVEC cells	ic50	0.0500	uM
4-methylpyridin-2-amine	68131: Inhibitory activity against endothelial nitric oxide synthase (eNOS)	ic50	0.0720	uM
5-ethynyl-4,5-dihydrothieno[2,3-c]pyridin-7-amine	85462: Ability to inhibit the conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by e-NOS from HUVEC cells	ic50	0.0800	uM
(2S)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepin-5-amine	1799391: NOS Enzyme Inhibition Assay from Article 10.1038/nchembio.115: “Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.”	ic50	0.0800	uM
2-[(4S)-4-amino-5-(2-aminoethylamino)pentyl]-1-nitroguanidine	414630: Inhibition of eNOS	ki	0.0800	uM
4-methylpyridine-2,3-diamine	68131: Inhibitory activity against endothelial nitric oxide synthase (eNOS)	ic50	0.0810	uM
N’-[(3S,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methyl]pyrrolidin-3-yl]-N-[(4-chlorophenyl)methyl]ethane-1,2-diamine	414630: Inhibition of eNOS	ki	0.0852	uM
N’-[(3R,4S)-4-[(6-amino-4-methyl-2-pyridinyl)methyl]pyrrolidin-3-yl]-N-[(3-chlorophenyl)methyl]ethane-1,2-diamine	414630: Inhibition of eNOS	ki	0.0952	uM
(2S)-2-amino-5-[[amino(nitramido)methylidene]amino]-N-[(2S)-1,4-diamino-1-oxobutan-2-yl]pentanamide	414630: Inhibition of eNOS	ki	0.1070	uM
(2S,4R)-4-[[(2S)-2-amino-5-[[amino(nitramido)methylidene]amino]pentanoyl]amino]pyrrolidine-2-carboxamide	414630: Inhibition of eNOS	ki	0.1100	uM
6-ethynyl-6,7-dihydrothieno[3,2-c]pyridin-4-amine	85462: Ability to inhibit the conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by e-NOS from HUVEC cells	ic50	0.1200	uM
4-methyl-2,3,4,5-tetrahydropyridin-6-amine	241405: Inhibitory activity against human Endothelial nitric oxide synthase (eNOS)	ic50	0.1460	uM
4-methyl-6-(2-methylpropyl)pyridin-2-amine	415183: Inhibition of human eNOS	ic50	0.1500	uM
3,4-dimethylpyridin-2-amine	68131: Inhibitory activity against endothelial nitric oxide synthase (eNOS)	ic50	0.1500	uM
8-fluoro-3-(4-fluorophenyl)-3,4-dihydroisoquinolin-1-amine	85322: Ability to inhibit conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by endothelial NOS (e NOS) from HUVEC cells	ic50	0.1600	uM
5,8-difluoro-2-(furan-2-yl)-1,2-dihydroquinazolin-4-amine	68135: Inhibitory activity against human endothelial nitric oxide synthase	ic50	0.1800	uM
N-[(5-chloro-2-nitrophenyl)methyl]-N,1-dimethylpiperidin-4-amine	316793: Inhibition of human eNOS expressed in insect SF9 cells after 1 hr	ic50	0.1800	uM
(3R)-3-propyl-2,3-dihydrothieno[2,3-f][1,4]oxazepin-5-amine	1799391: NOS Enzyme Inhibition Assay from Article 10.1038/nchembio.115: “Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.”	ic50	0.2000	uM
(3S)-3-propyl-2,3-dihydrothieno[2,3-f][1,4]oxazepin-5-amine	693738: Inhibition of wild type human eNOS using L-Arg as substrate incubated for 1 hr prior to L-Arg addition	ic50	0.2000	uM
4-methyl-6-propan-2-ylpyridin-2-amine	68131: Inhibitory activity against endothelial nitric oxide synthase (eNOS)	ic50	0.2000	uM
4-chloro-2-[[methyl-[1-(2-phenylethyl)piperidin-4-yl]amino]methyl]benzonitrile	316793: Inhibition of human eNOS expressed in insect SF9 cells after 1 hr	ic50	0.2200	uM
4-ethylpyridin-2-amine	68131: Inhibitory activity against endothelial nitric oxide synthase (eNOS)	ic50	0.2300	uM
4-methyl-2,3-dihydropyridin-6-amine	67822: Inhibition of human endothelial Nitric Oxide Synthase expressed in Sf-21 cells	ic50	0.2300	uM
2,4-dimethyl-2,3-dihydropyridin-6-amine	67822: Inhibition of human endothelial Nitric Oxide Synthase expressed in Sf-21 cells	ic50	0.2400	uM
(2R)-azetidine-2-carboximidamide	600731: Inhibition of human recombinant eNOS by microtiter plate assay	ic50	0.2500	uM
4,5-dihydrothieno[2,3-c]pyridin-7-amine	85462: Ability to inhibit the conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by e-NOS from HUVEC cells	ic50	0.2800	uM
(2S)-2-amino-5-[(N’-methylcarbamimidoyl)amino]pentanoic acid	85322: Ability to inhibit conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by endothelial NOS (e NOS) from HUVEC cells	ic50	0.3000	uM
2,4-dimethyl-2,3,4,5-tetrahydropyridin-6-amine	68142: inhibition of human endothelial constitutive Endothelial nitric oxide synthase (heNOS)	ic50	0.3000	uM
4,5-dimethyl-2,3-dihydropyridin-6-amine	67822: Inhibition of human endothelial Nitric Oxide Synthase expressed in Sf-21 cells	ic50	0.3200	uM
N’-[3-(aminomethyl)phenyl]-2-methylsulfanylethanimidamide;dihydrobromide	68156: Inhibitory activity against human endothelial nitric oxide synthase (eNOS) isoenzyme.	ki	0.3200	uM
N’-[3-(aminomethyl)phenyl]furan-2-carboximidamide;dihydrobromide	68156: Inhibitory activity against human endothelial nitric oxide synthase (eNOS) isoenzyme.	ki	0.3500	uM
N’-[3-(aminomethyl)phenyl]furan-2-carboximidamide	2007183: Inhibition of human eNOS assessed as reduction of L-[14C]arginine to L-[14C]-citrulline conversion	ki	0.3500	uM
(4R,4aR,7aR)-4-methyl-4,4a,5,6,7,7a-hexahydro-3H-cyclopenta[b]pyridin-2-amine	241405: Inhibitory activity against human Endothelial nitric oxide synthase (eNOS)	ic50	0.3600	uM
4-methyl-2-prop-2-enyl-2,3-dihydropyridin-6-amine	67822: Inhibition of human endothelial Nitric Oxide Synthase expressed in Sf-21 cells	ic50	0.3600	uM
3-[[(3S,4S)-4-[(6-amino-2-pyridinyl)methyl]pyrrolidin-3-yl]amino]propan-1-ol	414630: Inhibition of eNOS	ki	0.3666	uM
6-[4-[2-[4-(2-methylpropyl)piperazin-1-yl]ethyl]phenyl]pyridin-2-amine	68133: Inhibitory activity against human endothelial nitric oxide synthase (eNOS)	ic50	0.3720	uM
(2S)-2-amino-5-[[amino(methylsulfanyl)methylidene]amino]pentanoic acid	241624: Inhibitory concentration against human endothelial nitric oxide synthase expressed in Sf-9 cells	ic50	0.4000	uM
ethyl N’-phenylcarbamimidothioate;hydroiodide	68155: Inhibitory activity against human vascular endothelial nitric oxide synthase.	ki	0.4000	uM
ethyl N’-phenylcarbamimidothioate	2007172: Inhibition of human eNOS assessed as reduction of L-[14C]arginine to L-[14C]citrulline conversion	ki	0.4000	uM
N’-[3-(aminomethyl)phenyl]thiophene-2-carboximidamide;dihydrobromide	68156: Inhibitory activity against human endothelial nitric oxide synthase (eNOS) isoenzyme.	ki	0.4000	uM
N’-[1-(2-pyrrolidin-1-ylethyl)-2,3-dihydroindol-5-yl]thiophene-2-carboximidamide;dihydrochloride	715215: Inhibition of recombinant human iNOS expressed in baculovirus-infected Sf9 cells assessed as conversion of [3H]-larginine to [3H]-L-citrulline preincubated for 15 mins measured after 45 mins by liquid scintillation counting	ic50	0.4100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects localization, affects phosphorylation, increases activity, increases abundance, decreases reaction (+11 more)	28
Nitric Oxide	decreases activity, increases chemical synthesis, increases expression, decreases phosphorylation, decreases chemical synthesis (+10 more)	21
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases phosphorylation, decreases expression, increases activity, decreases degradation (+5 more)	13
Glucose	decreases phosphorylation, decreases reaction, increases expression, increases abundance, decreases expression (+4 more)	11
bisphenol A	affects binding, affects cotreatment, decreases methylation, decreases expression, increases expression (+2 more)	10
Hydrogen Peroxide	decreases expression, decreases reaction, affects cotreatment, increases expression, decreases activity (+5 more)	10
Wortmannin	increases expression, increases reaction, increases abundance, decreases reaction, increases activity (+3 more)	8
Simvastatin	decreases reaction, increases expression, increases phosphorylation, increases reaction, decreases expression (+2 more)	8
U 0126	increases phosphorylation, increases activity, increases abundance, affects reaction, decreases expression (+1 more)	6
Fulvestrant	decreases methylation, decreases reaction, increases expression, increases phosphorylation, increases abundance (+1 more)	6
Estradiol	affects cotreatment, increases expression, increases phosphorylation, increases chemical synthesis, decreases reaction (+2 more)	6
Plant Extracts	increases phosphorylation, increases response to substance, decreases expression, decreases reaction, increases expression (+1 more)	6
Quercetin	decreases expression, decreases reaction, increases phosphorylation, increases expression	6
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	decreases reaction, increases expression, increases phosphorylation, increases abundance	4
dorsomorphin	decreases phosphorylation, decreases reaction, increases activity, increases phosphorylation, increases expression	4
Atorvastatin	decreases expression, decreases reaction, increases expression, increases reaction, affects response to substance	4
Acetylcysteine	decreases reaction, increases expression, decreases expression	4
Calcium	increases activity, increases expression, decreases reaction, increases phosphorylation, affects reaction	4
Oxygen	decreases reaction, increases expression, decreases expression, decreases activity	4
Tobacco Smoke Pollution	decreases expression, increases expression, decreases phosphorylation	4
Genistein	decreases reaction, increases expression, decreases expression, increases activity	4
Rosiglitazone	decreases phosphorylation, decreases reaction, increases abundance, increases phosphorylation	3
Arsenic Trioxide	decreases expression, increases expression, increases activity, increases phosphorylation	3
Air Pollutants	increases abundance, increases expression, affects response to substance, decreases methylation	3
Benzo(a)pyrene	decreases reaction, affects methylation, increases methylation, increases phosphorylation	3
Dibutyl Phthalate	increases phosphorylation, decreases reaction, decreases phosphorylation, increases expression	3
Folic Acid	affects cotreatment, decreases expression, affects phosphorylation, decreases reaction, decreases activity	3
Methotrexate	decreases expression, increases expression, affects response to substance	3
Progesterone	decreases expression, decreases reaction, increases activity, increases reaction, increases expression (+1 more)	3
Superoxides	affects chemical synthesis, decreases reaction, increases abundance, increases reaction, increases activity (+2 more)	3

ChEMBL screening assays

188 unique, capped per target: 178 binding, 6 admet, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL675570	Binding	Ratio of Endothelial Nitric Oxide Synthase to Inducible nitric oxide synthase	Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. — Bioorg Med Chem Lett
CHEMBL4032165	ADMET	Inhibition of human endothelial NOS expressed in Escherichia coli using L-arginine as substrate assessed as reduction in NO production by measuring oxidation of oxyHb to metHb measured for 6 mins by hemoglobin- NO capture assay	Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. — J Med Chem
CHEMBL690699	Functional	Ability to inhibit conversion of [3H]L-Arg to [3H]L-citrulline catalyzed by endothelial NOS (e NOS) from HUVEC cells	3,4-Dihydro-1-isoquinolinamines: a novel class of nitric oxide synthase inhibitors with a range of isoform selectivity and potency. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8RI	Ubigene HCT 116 NOS3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00009191	PHASE4	COMPLETED	The Depression in Alzheimer’s Disease Study (DIADS)
NCT00009217	PHASE4	COMPLETED	Treatment of Behavioral Symptoms in Alzheimer’s Disease
NCT00018278	PHASE4	COMPLETED	Electrophysiologic Measures of Treatment Response in Alzheimer Disease
NCT00035204	PHASE4	COMPLETED	A Study of the Effects on Sleep, Attention, and Gastrointestinal Tolerance of Galantamine and Donepezil in Patients With Alzheimer’s Disease
NCT00042172	PHASE4	COMPLETED	Treatment for Early Memory Loss
NCT00046358	PHASE4	COMPLETED	The Effect of Short-Term Statins and NSAIDs on Levels of Beta-Amyloid, a Protein Associated With Alzheimer’s Disease
NCT00104442	PHASE4	COMPLETED	Study of the Effects of Current Drug Treatments on Levels of Certain Brain Chemicals in Alzheimer’s Disease
NCT00120874	PHASE4	COMPLETED	Memantine and Comprehensive, Individualized Management of Alzheimer’s Disease and Caregiver Training
NCT00142324	PHASE4	UNKNOWN	CALM-AD
NCT00165724	PHASE4	COMPLETED	Alzheimer’s Disease Long-term Follow-up Study (ALF Study)
NCT00165750	PHASE4	TERMINATED	Correlation Between Regional Brain Volume and Response to Donepezil Treatment in AD Patients
NCT00202124	PHASE4	COMPLETED	Double Blind Study of Trp01 in Patients With Alzheimer’s Disease
NCT00208819	PHASE4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00216515	PHASE4	COMPLETED	The Efficacy of Galantamine on the Attention and the Frontal Function of the Patients With Dementia of Alzheimer Type
NCT00230568	PHASE4	COMPLETED	EARTH 413: A Study of Aricept in Hispanic Patients With Mild to Moderate Alzheimer’s Disease (AD)
NCT00234637	PHASE4	COMPLETED	Rivastigmine Monotherapy and Combination Therapy With Memantine in Patients With Moderately Severe Alzheimer’s Disease Who Failed to Benefit From Previous Cholinesterase Inhibitor Treatment
NCT00245206	PHASE4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	PHASE4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00260624	PHASE4	COMPLETED	Escitalopram Treatment of Patients With Agitated Dementia
NCT00303277	PHASE4	COMPLETED	Do HMG CoA Reductase Inhibitors Affect Abeta Levels?
NCT00305903	PHASE4	COMPLETED	Safety and Tolerability of Rivastigmine With Add-on Memantine in Patients With Probable Alzheimer’s Disease
NCT00306124	PHASE4	UNKNOWN	Dopaminergic Enhancement of Learning and Memory in Healthy Adults and Patients With Dementia/Mild Cognitive Impairment
NCT00334906	PHASE4	COMPLETED	Study of Memantine in Assessment of Selected Measures of Volumetric Magnetic Resonance Imaging (MRI) and Cognition in Moderate AD (Alzheimer’s Disease)
NCT00369603	PHASE4	TERMINATED	Functional Brain Imaging of Medication Treatment Response in Mild Alzheimer’s Disease Patients
NCT00375557	PHASE4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00381381	PHASE4	COMPLETED	The Clinical Response of Choline Acetyltransferase and Apolipoprotein Epsilon Gene Polymorphisms to Donepezil in Alzheimer’s Disease
NCT00385684	PHASE4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00401167	PHASE4	COMPLETED	Memantine for Agitation and Aggression in Severe Alzheimer’s Disease
NCT00403520	PHASE4	COMPLETED	Hippocampus Study: Comparative Effect of Donepezil 10mg/d and Placebo on Clinical and Radiological Markers
NCT00417482	PHASE4	COMPLETED	Antipsychotic Discontinuation in Alzheimer’s Disease
NCT00443014	PHASE4	COMPLETED	The Dementia Study in Northern Norway
NCT00469456	PHASE4	COMPLETED	Effect of Memantine on Functional Communication in Patients With Alzheimer’s Disease
NCT00476008	PHASE4	COMPLETED	Delaying the Progression of Driving Impairment in Individuals With Mild Alzheimer’s Disease
NCT00477659	PHASE4	COMPLETED	Neural Correlates In Mild Alzheimer’s Disease
NCT00480870	PHASE4	COMPLETED	The Effect of Anticholinesterase Drugs on Sleep in Alzheimer’s Disease Patients
NCT00495820	PHASE4	COMPLETED	Methylphenidate for Apathy in Alzheimer’s Dementia: A Controlled Study
NCT00523666	PHASE4	UNKNOWN	Diffusion Tensor Weighted MRI in Alzheimer’s Disease Modifying Treatment Effects of Galantamine (Reminyl®)
NCT00549601	PHASE4	COMPLETED	Convenience, Tolerability, and Safety of Change in the Administration of Rivastigmine From Capsules to a Transdermal Patch in Patients With Mild to Moderate Alzheimer’s Disease
NCT00551161	PHASE4	COMPLETED	Magnetic Resonance Spectroscopy Study of Memantine in Alzheimer’s Disease
NCT00561392	PHASE4	COMPLETED	Clinical Effectiveness of 10 cm^2 Rivastigmine Patch in Patients With Alzheimer’s Disease