MC4R

Summary

MC4R (melanocortin 4 receptor, HGNC:6932) is a protein-coding gene on chromosome 18q21.32, encoding Melanocortin receptor 4 (P32245). G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor.

The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity.

Source: NCBI Gene 4160 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited obesity (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 181
• Clinical variants (ClinVar): 286 total — 26 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes — 57 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005912

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6932
Approved symbol	MC4R
Name	melanocortin 4 receptor
Location	18q21.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166603
Ensembl biotype	protein_coding
OMIM	155541
Entrez	4160

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000299766

RefSeq mRNA: 1 — MANE Select: NM_005912 NM_005912

CCDS: CCDS11976

Canonical transcript exons

ENST00000299766 — 1 exons

Exon	Start	End
ENSE00001104613	60371062	60372775

Expression profiles

Bgee: expression breadth broad, 69 present calls, max score 69.78.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6964 / max 135.8167, expressed in 201 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172216	2.5363	195
172217	0.1601	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	69.78	silver quality
right uterine tube	UBERON:0001302	69.02	gold quality
prefrontal cortex	UBERON:0000451	63.46	gold quality
hypothalamus	UBERON:0001898	63.21	gold quality
caudate nucleus	UBERON:0001873	62.49	gold quality
anterior cingulate cortex	UBERON:0009835	62.03	gold quality
cingulate cortex	UBERON:0003027	61.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	60.55	gold quality
putamen	UBERON:0001874	60.22	gold quality
neocortex	UBERON:0001950	57.41	gold quality
frontal cortex	UBERON:0001870	56.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	56.89	gold quality
oviduct epithelium	UBERON:0004804	55.29	silver quality
nucleus accumbens	UBERON:0001882	55.07	gold quality
right frontal lobe	UBERON:0002810	54.85	gold quality
telencephalon	UBERON:0001893	54.73	gold quality
amygdala	UBERON:0001876	54.54	gold quality
cerebral cortex	UBERON:0000956	54.17	gold quality
cortical plate	UBERON:0005343	53.33	gold quality
forebrain	UBERON:0001890	53.20	gold quality
tibialis anterior	UBERON:0001385	53.11	silver quality
fallopian tube	UBERON:0003889	53.03	gold quality
bone marrow cell	CL:0002092	52.90	gold quality
epithelial cell of pancreas	CL:0000083	52.89	gold quality
primary visual cortex	UBERON:0002436	51.11	gold quality
brain	UBERON:0000955	50.90	gold quality
upper leg skin	UBERON:0004262	50.64	silver quality
deltoid	UBERON:0001476	50.43	gold quality
ileal mucosa	UBERON:0000331	49.57	silver quality
quadriceps femoris	UBERON:0001377	49.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NHLH2

Literature-anchored findings (GeneRIF, showing 40)

• Because it has no introns, the gene is insensitive to the normal degradation of mRNA’s with premature termination codons. (PMID:11823452)
• molecular determinants responsible for antagonist SHU9119 selective activity (PMID:11912210)
• MC4R obesity causing mutations in less than 0.5% of the patients indicate low prevalence of MC4R variants in the obese population from southern Italy (PMID:12032748)
• Identification of domains directing specificity of coupling to G-proteins (PMID:12045190)
• MC4R mutation screen in bulimia nervosa patients (PMID:12140789)
• the function of the MC1 and MC4 receptors can be positively modulated by metal ions acting both as partial agonists and as potentiators for other agonists (PMID:12244039)
• results do not support the prevailing notion that sequence variation in the melanocortin 4 receptor gene is a frequent cause of human obesity (PMID:12364415)
• Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity . (PMID:12499395)
• the impact of the MC4R mutations on receptor function and for the development of obesity (PMID:12690102)
• beta-MSH rather than alpha-MSH is the key ligand at the MC4-R populations that regulate feeding, and inhibition of tonic release of beta-MSH is one mechanism contributing to hunger in under-feeding (PMID:12732337)
• The second and third extracellular loops of MC4R are important for AGRP 87-132 N-terminal binding, whereas the third and fourth transmembrane domains of hMC4R are crucial for AGRP 110-117 binding. (PMID:12815165)
• Six of 11 mutants had either decreased or no ligand binding, with proportional impairments in [Nle4, d-Phe7]-alpha-MSH-stimulated cAMP production. (PMID:12959994)
• Melanocortin-4 receptor gene mutations represent major gene effects for obesity (PMID:12970296)
• A three-dimensional structure of the human melanocortin 4 receptor (hMC4R) is constructed in this study using a computer-aided molecular modeling approach. (PMID:13678297)
• identification of missense mutation in patients with early onset obesity (PMID:14504270)
• unlocking of a stabilizing interaction between the DRY motif, in the cytosolic part of transmembrane region TM3, and TM6 is important for the activation process; unlocking may be facilitated by creation of a new interaction between TM3 and TM2 (PMID:14523020)
• Genetic variation in the transcriptionally essential region of the MC4R promoter is not a significant cause of severe obesity in humans. (PMID:14633862)
• A novel heterozygous missense mutation (Glu(308)Lys) that impairs MC4-R functional activity in vitro was characterized. (PMID:14764812)
• Pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of S127L receptor due to reduced activation. (PMID:14764818)
• No evidence for an increased rate of binge-eating behavior in obese carriers of MC4R variants. (PMID:15037865)
• In humans, MC4R mediates most anorectic effects of leptin in early childhood. Does not mediate effect of leptin on linear growth and other endocrine axes. MC4R deficiency not cause of relative hyperinsulinemia. (PMID:15126516)
• While no MC4R ligand binding was detected in any of the mutants studied, one mutant, D146A, resulted in higher cAMP production in cells than the wild-type receptor without ligand stimulation (PMID:15215606)
• the Val103Ile polymorphism of the melanocortin-4 receptor (MC4R) gene is associated with energy expenditure in humans (PMID:15292469)
• Variations in MC4R may account for a small portion of obesity in Pima Indians. (PMID:15448103)
• findings clearly substantiate that MC4R mutations entail a strong predisposition to obesity (PMID:15466016)
• Outlining the ligand recognition sites in the melanocortin receptors. (PMID:15470082)
• Results suggest that the tonic satiety signal provided by the constitutive activity of the melanocortin-4 receptor may be required for maintaining long-term energy homeostasis in humans. (PMID:15489963)
• DNA sequence analysis of the conformers of melanocortin-4 receptor (MC4R) revealed variants in premature pubarche and hyperandrogenism. (PMID:15533382)
• Data demonstrate that the constitutive activity of the human melanocortin-4 receptor promoter is dependent upon Sp1 and 3 transcription factors. (PMID:15821099)
• The proximal region of the melanocortin-4 receptor (MC4R) carboxyl-terminus is crucial not only for receptor signaling but also for ligand binding, while the third intracellular loop is important mainly for receptor signaling. (PMID:15865442)
• Novel MC4R variant identified from an obese patient cannot be assumed to be the cause of obesity without demonstrating a loss-of-function phenotype (PMID:16030156)
• Dermal papilla cells expressed both MC1R and MC4R in vitro, and immunoreactivity for these receptors was also present in cells of the human dermal papilla in situ. (PMID:16081629)
• Systematic and comparative functional study of over 50 different obesity-associated MC4R mutations highlighted in this review suggests that multiple functional alterations contribute to their pathogenicity. (PMID:16083993)
• Binding affinity and potency of the linear peptide agonists, while site directed mutation impaired interactions with nonpeptide agonists. (PMID:16114870)
• Melanocortin 4 receptor (MC4R) residue leucine-250 is proposed as a key role-player in switching MC4R from active to inactive receptor conformation. (PMID:16611215)
• CART signaling is the main molecular pathway accounting for the decrease in bone resorption leading to high bone mass in mice and humans deficient in Mc4r (PMID:16614075)
• A MC4R promoter mutation, -439delGC, associated with early-onset obesity. (PMID:16710097)
• analysis of molecular basis of melanocortin-4 receptor for AGRP inverse agonism (PMID:16820227)
• in addition to its inverse agonistic activities, Agrp exhibits agonistic properties on the endocytosis pathway of melanocortin-3 and -4 receptors (PMID:17041250)
• Two novel heterozygous non-synonymous mutations (Val166Ile; Arg310Lys) and a novel heterozygous non-sense mutation (Cys277Stop) in the melanocortin 4 receptor were detected in Chinese obese individuals. (PMID:17185898)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	mc4r	ENSDARG00000015515
mus_musculus	Mc4r	ENSMUSG00000047259

Paralogs (18): LPAR2 (ENSG00000064547), CNR1 (ENSG00000118432), MC3R (ENSG00000124089), S1PR4 (ENSG00000125910), GPR12 (ENSG00000132975), GPR6 (ENSG00000146360), GPR119 (ENSG00000147262), S1PR1 (ENSG00000170989), LPAR3 (ENSG00000171517), MC5R (ENSG00000176136), S1PR5 (ENSG00000180739), GPR3 (ENSG00000181773), MC2R (ENSG00000185231), CNR2 (ENSG00000188822), LPAR1 (ENSG00000198121), S1PR3 (ENSG00000213694), MC1R (ENSG00000258839), S1PR2 (ENSG00000267534)

Protein

Protein identifiers

Melanocortin receptor 4 — P32245 (reviewed: P32245)

All UniProt accessions (1): P32245

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor. Functions as a central component of the leptin-melanocortin pathway, which is essential for maintaining energy homeostasis. Upon activation, couples to G(s) protein, stimulating adenylate cyclase and the cAMP-dependent signaling pathway, which promotes anorexogenic signaling in the hypothalamus and contributes to a negative energy balance. Regulates food intake: activation by agonists suppresses appetite, whereas the antagonist Agouti-related protein/AGRP precludes agonist-induced signaling, thereby stimulating appetite. Modulates the firing activity of neurons in paraventricular nucleus (PVN) of the hypothalamus via alpha-MSH and AGRP regulation of inwardly rectifying potassium channel KCNJ13 closure, independently of G(s) signaling. In the PVN, also interacts with opsin 3/OPN3, which couples to G(i/o) proteins to inhibit MC4R-mediated cAMP signaling, thereby promoting food intake. In intestinal epithelial cells, contributes to inhibition of hepatic glucose production via nesfatin-1/NUCB2, leading to increased cAMP levels and glucagon-like peptide 1 (GLP-1) secretion. Interaction with MGRN1 displaces the G(s) protein, further decreasing MC4R signaling activity. Also activated by gamma-MSH, though with low potency.

Subunit / interactions. Homodimer; disulfide-linked, also forms higher order oligomers. Interacts with GNAS. Interacts with ATRNL1. Interacts with MGRN1; this interaction competes with GNAS-binding and thus inhibits agonist-induced cAMP production. Interacts with MRAP and MRAP2; these associated factors increase ligand-sensitivity and generation of cAMP. Forms a complex with OPN3 and KCNJ13; interaction with OPN3 inhibits MC4R-mediated signaling.

Subcellular location. Cell membrane.

Tissue specificity. Brain, placental, and gut tissues.

Disease relevance. Obesity (OBESITY) [MIM:601665] A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in MC4R define the body mass index quantitative trait locus 20 (BMIQ20) [MIM:618406]. MC4R loss-of-function variants are associated with higher body mass index, obesity, type 2 diabetes, and coronary artery disease. Gain-of-function variants have been reported to be associated with lower body mass index and resistance to obesity.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_005903* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000155	Mcort_rcpt_4	Family
IPR000276	GPCR_Rhodpsn	Family
IPR001671	Melcrt_ACTH_rcpt	Family
IPR001908	MC3-5R	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (79 total): sequence variant 34, helix 12, topological domain 8, transmembrane region 7, mutagenesis site 4, binding site 3, glycosylation site 3, disulfide bond 3, turn 2, chain 1, lipid moiety-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7PIU	ELECTRON MICROSCOPY	2.58
6W25	X-RAY DIFFRACTION	2.75
7PIV	ELECTRON MICROSCOPY	2.86
8WKY	X-RAY DIFFRACTION	2.9
7AUE	ELECTRON MICROSCOPY	2.97
7F53	ELECTRON MICROSCOPY	3
7F54	ELECTRON MICROSCOPY	3
7F55	ELECTRON MICROSCOPY	3.1
7F58	ELECTRON MICROSCOPY	3.1
9K3K	ELECTRON MICROSCOPY	3.12
8WKZ	X-RAY DIFFRACTION	3.3
8QJ2	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32245-F1	80.21	0.48

Antibody-complex structures (SAbDab): 9 — 7AUE, 7F53, 7F54, 7F55, 7F58, 7PIU, 7PIV, 8QJ2, 9K3K

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 (3): 100; 122; 126

Post-translational modifications (1): 318

Disulfide bonds (3): 40–279, 84, 271–277

Glycosylation sites (3): 3, 17, 26

Mutagenesis-validated functional residues (4):

Position	Phenotype
100	almost complete loss of alpha-msh signaling.
122	loss of high-affinity ligand binding.
122	about 50% loss of alpha-msh signaling.
126	complete abolishment of receptor function.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding
R-HSA-9730414	MITF-M-regulated melanocyte development

MSigDB gene sets: 135 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_BEHAVIOR, GOBP_INSULIN_SECRETION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RESPONSE_TO_FOOD, GOBP_HORMONE_TRANSPORT, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_REGULATION_OF_BEHAVIOR, GOBP_REGULATION_OF_FEEDING_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_EATING_BEHAVIOR, GOBP_RESPONSE_TO_INSULIN

GO Biological Process (13): adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), feeding behavior (GO:0007631), insulin secretion (GO:0030073), response to food (GO:0032094), response to insulin (GO:0032868), positive regulation of bone resorption (GO:0045780), regulation of feeding behavior (GO:0060259), regulation of eating behavior (GO:1903998), negative regulation of eating behavior (GO:1903999), response to melanocyte-stimulating hormone (GO:1990680), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (7): melanocortin receptor activity (GO:0004977), corticotropin receptor activity (GO:0004978), melanocyte-stimulating hormone receptor activity (GO:0004980), ubiquitin protein ligase binding (GO:0031625), neuropeptide binding (GO:0042923), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
MITF-M-regulated melanocyte development	1
Signal Transduction	1
GPCR ligand binding	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
response to peptide hormone	2
eating behavior	2
melanocortin receptor activity	2
hormone binding	2
cellular anatomical structure	2
adenylate cyclase activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
behavior	1
protein secretion	1
peptide hormone secretion	1
response to nutrient levels	1
response to chemical	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
feeding behavior	1
regulation of behavior	1
regulation of feeding behavior	1
regulation of eating behavior	1
negative regulation of feeding behavior	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
G protein-coupled peptide receptor activity	1
neuropeptide receptor activity	1
ubiquitin-like protein ligase binding	1
peptide binding	1
transmembrane signaling receptor activity	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1856 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MC4R	POMC	P01189	999
MC4R	AGRP	O00253	997
MC4R	LEP	P41159	945
MC4R	FTO	Q9C0B1	945
MC4R	TMEM18	Q96B42	928
MC4R	NPY	P01303	915
MC4R	KCTD15	Q96SI1	907
MC4R	GHRL	Q9UBU3	884
MC4R	LEPR	P48357	882
MC4R	LCN2	P30150	877
MC4R	GNPDA2	Q8TDQ7	874
MC4R	ATRN	O75882	868
MC4R	SH2B1	Q9NRF2	867
MC4R	PCSK1	P29120	851
MC4R	SIM1	P81133	839

IntAct

16 interactions, top by confidence:

A	B	Type	Score
MRAP	MC4R	psi-mi:“MI:0915”(physical association)	0.400
MRAP2	MC4R	psi-mi:“MI:0915”(physical association)	0.400
AIG1	MC4R	psi-mi:“MI:0915”(physical association)	0.370
ATP6V0E2	MC4R	psi-mi:“MI:0915”(physical association)	0.370
CD81	MC4R	psi-mi:“MI:0915”(physical association)	0.370
TMEM94	MC4R	psi-mi:“MI:0915”(physical association)	0.370
MAL	MC4R	psi-mi:“MI:0915”(physical association)	0.370
NPC1	MC4R	psi-mi:“MI:0915”(physical association)	0.370
PLLP	MC4R	psi-mi:“MI:0915”(physical association)	0.370
PDIA6	MC4R	psi-mi:“MI:0915”(physical association)	0.370
TSPAN3	MC4R	psi-mi:“MI:0915”(physical association)	0.370
TMEM19	MC4R	psi-mi:“MI:0915”(physical association)	0.370
YIPF3	MC4R	psi-mi:“MI:0915”(physical association)	0.370
MC4R	IL1RAP	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (20): MC4R (Reconstituted Complex), MC4R (Synthetic Lethality), AIG1 (Two-hybrid), ATP6V0E2 (Two-hybrid), CD81 (Two-hybrid), KIAA0195 (Two-hybrid), MAL (Two-hybrid), NPC1 (Two-hybrid), PLLP (Two-hybrid), PDIA6 (Two-hybrid), TSPAN3 (Two-hybrid), TMEM19 (Two-hybrid), YIPF3 (Two-hybrid), MC4R (Reconstituted Complex), MC4R (Reconstituted Complex)

ESM2 similar proteins: B0V1P1, O19037, O77616, O97504, P32244, P32245, P33032, P33033, P34974, P35345, P41149, P41968, P41983, P55167, P56442, P56450, P56451, P70115, P70596, P79166, Q01718, Q01727, Q0Z8I9, Q29154, Q64326, Q6A155, Q80SS9, Q80SZ5, Q864F7, Q864F8, Q864G9, Q864H1, Q864H2, Q864H3, Q864H4, Q864H5, Q864I1, Q864I2, Q864I3, Q864K7

Diamond homologs: B0V1P1, O19037, O77616, O97504, P32244, P32245, P33032, P33033, P34974, P35345, P41149, P41968, P41983, P47798, P55167, P56442, P56443, P56444, P56445, P56446, P56447, P56448, P56450, P56451, P70115, P70596, P79166, Q01718, Q01726, Q01727, Q0Q460, Q0Z8I9, Q29154, Q64326, Q6A155, Q80SS9, Q80SZ5, Q864F4, Q864F5, Q864F6

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
GRK2	“down-regulates activity”	MC4R	phosphorylation
PRKACA	“down-regulates activity”	MC4R	phosphorylation
POMC	“up-regulates activity”	MC4R	binding
AGRP	“down-regulates activity”	MC4R	binding
MC4R	“up-regulates activity”	GNAS
MC4R	“up-regulates activity”	GNAS	binding
MC4R	“up-regulates activity”	GNAL	binding
MC4R	“up-regulates activity”	GNAI1	binding
MC4R	“up-regulates activity”	GNAI3	binding
MC4R	“up-regulates activity”	GNAZ	binding
MC4R	“up-regulates activity”	GNAQ	binding
MC4R	“up-regulates activity”	GNA14	binding
MC4R	“up-regulates activity”	GNA12	binding
“MSH release-inhibiting hormone”	“up-regulates activity”	MC4R	“chemical activation”
MC4R	down-regulates	“Food intake”
ASIP	“down-regulates activity”	MC4R	binding
Corticotropin	“up-regulates activity”	MC4R	binding
AGRP	down-regulates	MC4R	binding
MRAP	“down-regulates activity”	MC4R	binding
MRAP2	“down-regulates activity”	MC4R	binding
“Melanotan II”	“up-regulates activity”	MC4R	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	25
Uncertain significance	157
Likely benign	30
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1301992	NM_005912.3(MC4R):c.268G>A (p.Asp90Asn)	Pathogenic
1323269	NM_005912.3(MC4R):c.831T>A (p.Cys277Ter)	Pathogenic
1328028	NM_005912.3(MC4R):c.240C>A (p.Tyr80Ter)	Pathogenic
14316	NM_005912.3(MC4R):c.631_634del (p.Leu211fs)	Pathogenic
14317	NM_005912.3(MC4R):c.732_735dup (p.Thr246fs)	Pathogenic
14318	NM_005912.2(MC4R):c.105C>A (p.Tyr35Ter)	Pathogenic
14321	NM_005912.3(MC4R):c.172A>T (p.Ser58Cys)	Pathogenic
14322	NM_005912.3(MC4R):c.305T>G (p.Ile102Ser)	Pathogenic
14325	MC4R, 1-BP INS, 112A	Pathogenic
14327	MC4R, 2-BP INS, 279GT	Pathogenic
14329	NM_005912.3(MC4R):c.812G>A (p.Cys271Tyr)	Pathogenic
14332	NM_005912.3(MC4R):c.861T>A (p.Tyr287Ter)	Pathogenic
14333	NM_005912.3(MC4R):c.289A>G (p.Asn97Asp)	Pathogenic
14335	NM_005912.3(MC4R):c.265_279del (p.Ala89_Val93del)	Pathogenic
211442	NM_005912.3(MC4R):c.206T>G (p.Ile69Arg)	Pathogenic
2634260	NM_005912.3(MC4R):c.343_344del (p.Gln115fs)	Pathogenic
2634476	NM_005912.3(MC4R):c.305T>C (p.Ile102Thr)	Pathogenic
3242797	NC_000018.9:g.(?58038584)(58040587_?)del	Pathogenic
3354801	NM_005912.3(MC4R):c.48dup (p.Asn17fs)	Pathogenic
3657668	NM_005912.3(MC4R):c.434dup (p.Asp146fs)	Pathogenic
4533312	NM_005912.3(MC4R):c.823C>T (p.Pro275Ser)	Pathogenic
4540613	NM_005912.3(MC4R):c.828_829del (p.Tyr276_Cys277delinsTer)	Pathogenic
492863	NM_005912.3(MC4R):c.838T>C (p.Phe280Leu)	Pathogenic
638110	GRCh37/hg19 18q21.32(chr18:57940764-58095560)x1	Pathogenic
945179	NM_005912.3(MC4R):c.902T>C (p.Ile301Thr)	Pathogenic
976165	NM_005912.3(MC4R):c.407C>T (p.Ser136Phe)	Pathogenic
1339319	NM_005912.3(MC4R):c.258G>T (p.Leu86Phe)	Likely pathogenic
14334	NM_005912.3(MC4R):c.185A>G (p.Asn62Ser)	Likely pathogenic
1693542	NM_005912.3(MC4R):c.127C>A (p.Gln43Lys)	Likely pathogenic
1693543	NM_005912.3(MC4R):c.272T>G (p.Met91Arg)	Likely pathogenic

SpliceAI

157 predictions. Top by Δscore:

Variant	Effect	Δscore
18:60371706:A:C	acceptor_gain	0.9200
18:60371481:A:T	acceptor_gain	0.7500
18:60372091:CCAAG:C	acceptor_gain	0.7200
18:60372092:CAAGC:C	acceptor_gain	0.7200
18:60372266:A:AC	donor_gain	0.6800
18:60372267:C:CC	donor_gain	0.6800
18:60372267:CTGG:C	donor_gain	0.6300
18:60372096:C:CC	acceptor_gain	0.6000
18:60371706:A:AC	acceptor_gain	0.5900
18:60372229:AGCAC:A	donor_gain	0.5700
18:60372092:CAAG:C	acceptor_gain	0.5300
18:60371961:CAGA:C	donor_gain	0.4800
18:60372094:AG:A	acceptor_gain	0.4800
18:60371705:CA:C	acceptor_gain	0.4600
18:60372198:A:AC	donor_gain	0.4600
18:60372266:ACTGG:A	donor_gain	0.4600
18:60372267:CTGGC:C	donor_gain	0.4600
18:60372671:T:A	donor_gain	0.4600
18:60371714:A:C	acceptor_gain	0.4500
18:60371699:C:CT	acceptor_gain	0.4400
18:60372267:CT:C	donor_gain	0.4400
18:60371991:T:C	donor_gain	0.4300
18:60372267:CTG:C	donor_gain	0.4300
18:60371708:G:C	acceptor_gain	0.4200
18:60371700:A:T	acceptor_gain	0.4100
18:60371451:A:T	acceptor_gain	0.4000
18:60371480:CAG:C	acceptor_gain	0.4000
18:60371905:AGTAC:A	donor_loss	0.4000
18:60371906:GTACC:G	donor_loss	0.4000
18:60371907:TA:T	donor_loss	0.4000

AlphaMissense

2203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:60372095:G:C	S85R	1.000
18:60372095:G:T	S85R	1.000
18:60372097:T:G	S85R	1.000
18:60371571:G:C	P260R	0.999
18:60371578:A:G	W258R	0.999
18:60371578:A:T	W258R	0.999
18:60371581:A:G	C257R	0.999
18:60371588:A:C	F254L	0.999
18:60371588:A:T	F254L	0.999
18:60371590:A:G	F254L	0.999
18:60371830:A:G	W174R	0.999
18:60371830:A:T	W174R	0.999
18:60371933:G:C	S139R	0.999
18:60371933:G:T	S139R	0.999
18:60371935:T:G	S139R	0.999
18:60372068:G:C	S94R	0.999
18:60372068:G:T	S94R	0.999
18:60372070:T:G	S94R	0.999
18:60372080:A:C	D90E	0.999
18:60372080:A:T	D90E	0.999
18:60372081:T:A	D90V	0.999
18:60372081:T:G	D90A	0.999
18:60372164:A:C	N62K	0.999
18:60372164:A:T	N62K	0.999
18:60372176:G:C	S58R	0.999
18:60372176:G:T	S58R	0.999
18:60372178:T:G	S58R	0.999
18:60371571:G:T	P260Q	0.998
18:60371579:G:C	C257W	0.998
18:60371580:C:T	C257Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000300412 (18:60371175 T>C), RS1001066259 (18:60372538 C>T), RS1002260901 (18:60373941 T>C), RS1003644404 (18:60370897 C>A,T), RS1004416559 (18:60371249 C>A,T), RS1004876335 (18:60370962 T>C), RS1005914711 (18:60370614 G>T), RS1006923331 (18:60372828 A>G), RS1006923386 (18:60371620 C>T), RS1007263582 (18:60374435 A>G), RS1007315816 (18:60374143 T>C), RS1007984541 (18:60371289 A>T), RS1008164546 (18:60372642 T>C), RS1009938037 (18:60372337 T>A), RS1010360717 (18:60372597 C>A,G)

Disease associations

OMIM: gene MIM:155541 | disease phenotypes: MIM:601665, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited obesity	Strong	Autosomal dominant
obesity due to melanocortin 4 receptor deficiency	Strong	Semidominant

Mondo (5): obesity due to melanocortin 4 receptor deficiency (MONDO:0019115), inherited obesity (MONDO:0019182), schizophrenia (MONDO:0005090), obesity disorder (MONDO:0011122), monogenic diabetes (MONDO:0015967)

Orphanet (5): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Genetic obesity (Orphanet:77828), Rare genetic diabetes mellitus (Orphanet:183625), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

14 total (15 of 14 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000098	Tall stature
HP:0000822	Hypertension
HP:0000842	Hyperinsulinemia
HP:0000956	Acanthosis nigricans
HP:0001513	Obesity
HP:0002155	Hypertriglyceridemia
HP:0002591	Polyphagia
HP:0005616	Accelerated skeletal maturation
HP:0005978	Type II diabetes mellitus
HP:0008915	Childhood-onset truncal obesity
HP:0009126	Increased adipose tissue
HP:0011001	Increased bone mineral density
HP:0100753	Schizophrenia

GWAS associations

181 associations (top):

Study	Trait	p-value
GCST000184_4	Waist circumference and related phenotypes	2.000000e-09
GCST000185_2	Body mass index	3.000000e-15
GCST000296_6	Body mass index	1.000000e-12
GCST000298_2	Body mass index	5.000000e-18
GCST000299_10	Weight	5.000000e-13
GCST000317_10	Obesity	4.000000e-09
GCST000317_8	Obesity	5.000000e-15
GCST000317_9	Obesity	2.000000e-08
GCST000427_3	Waist circumference	4.000000e-07
GCST000663_1	Obesity (early onset extreme)	6.000000e-11
GCST000755_26	HDL cholesterol	7.000000e-09
GCST000817_156	Height	4.000000e-11
GCST000830_2	Body mass index	6.000000e-42
GCST001288_2	Obesity-related traits	6.000000e-06
GCST001416_5	Body mass index (SNP x SNP interaction)	2.000000e-11
GCST001517_1	Antipsychotic drug-induced weight gain	6.000000e-12
GCST001791_14	Urate levels	2.000000e-06
GCST001953_19	Obesity	2.000000e-36
GCST001953_25	Obesity	3.000000e-22
GCST001953_48	Obesity	2.000000e-27
GCST001955_2	Body mass index	4.000000e-21
GCST001957_14	Obesity (early onset extreme)	9.000000e-14
GCST002021_12	Body mass index	4.000000e-17
GCST002223_28	HDL cholesterol	4.000000e-08
GCST002226_1	Fat body mass	3.000000e-11
GCST002227_1	Body mass index	8.000000e-19
GCST002301_1	Body mass index	7.000000e-07
GCST002352_40	Type 2 diabetes	3.000000e-08
GCST002461_11	Body mass index	7.000000e-14
GCST002647_157	Height	7.000000e-13

EFO canonical traits (32, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004338	body weight
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004567	antipsychotic drug related weight gain
EFO:0004531	urate measurement
EFO:0005937	longitudinal BMI measurement
EFO:0007800	body fat percentage
EFO:0007828	daytime rest measurement
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement
EFO:0004343	waist-hip ratio
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0006941	grip strength measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007785	femoral neck bone mineral density
EFO:0007933	radius bone mineral density
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0006336	diastolic blood pressure
EFO:0007041	obese body mass index status
EFO:0004329	alcohol drinking
EFO:0010078	dentures
EFO:0006781	coffee consumption measurement
EFO:0007777	base metabolic rate measurement
EFO:0000195	metabolic syndrome
EFO:0006782	cups of coffee per day measurement
EFO:0008111	diet measurement
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2111323 (SELECTIVITY GROUP), CHEMBL2111397 (SELECTIVITY GROUP), CHEMBL2111423 (SELECTIVITY GROUP), CHEMBL259 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

57 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 478,914 (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
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL111	RIMONABANT	4	15,726
CHEMBL1172	DESLORATADINE	4	19,720
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1200485	SORAFENIB TOSYLATE	4	30,403
CHEMBL1200515	DESERPIDINE	4	2,483
CHEMBL1201309	NAFARELIN	4
CHEMBL1201469	GRAMICIDIN	4
CHEMBL121	ROSIGLITAZONE	4	58,849
CHEMBL122	ROFECOXIB	4	66,907
CHEMBL1305	ANTAZOLINE	4	9,182
CHEMBL1373	MODAFINIL	4	14,293
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL1491	AMLODIPINE	4	39,495
CHEMBL1617	RIFAXIMIN	4	13,380
CHEMBL1626	CLEMASTINE	4	17,590
CHEMBL17157	TERFENADINE	4	25,393
CHEMBL2010601	IVACAFTOR	4	2,662
CHEMBL2070241	BREMELANOTIDE	4
CHEMBL2103784	COSYNTROPIN	4
CHEMBL237500	LINAGLIPTIN	4
CHEMBL24072	PRENYLAMINE	4
CHEMBL249837	METHACYCLINE	4
CHEMBL288441	BOSUTINIB	4
CHEMBL296419	ASTEMIZOLE	4
CHEMBL32800	FENOTEROL	4
CHEMBL3301624	SETMELANOTIDE	4
CHEMBL415	CLOMIPRAMINE	4

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

PharmGKB clinical annotations

14 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11872992	Toxicity	3	clozapine	Schizophrenia
rs11872992	Toxicity	3	olanzapine	Schizophrenia;Weight gain
rs17782313	Toxicity	3	antipsychotics	Weight gain
rs17782313	Toxicity	3	paliperidone	Weight gain
rs17782313	Toxicity	3	quetiapine	Weight gain
rs17782313	Toxicity	3	risperidone	Weight gain
rs17782313	Toxicity	3	amisulpride	Weight gain
rs489693	Toxicity	3	antipsychotics	Weight gain
rs489693	Efficacy	3	paliperidone	Weight gain
rs489693	Toxicity	3	haloperidol	Hypertriglyceridemia;Schizoaffective disorder;Schizophrenia;Weight gain
rs489693	Toxicity	3	risperidone	Weight gain
rs489693	Toxicity	3	amisulpride	Hypertriglyceridemia;Weight gain
rs489693	Toxicity	3	aripiprazole	Weight gain
rs489693	Toxicity	3	quetiapine	Hypertriglyceridemia;Schizoaffective disorder;Schizophrenia;Weight gain

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs489693	MC4R	3	4.88	7	amisulpride;haloperidol;quetiapine;paliperidone;risperidone;aripiprazole;antipsychotics
rs8087522	MC4R		0.00	0
rs11872992	MC4R	3	0.00	2	clozapine;olanzapine
rs17782313	MC4R	3	3.50	5	quetiapine;paliperidone;risperidone;amisulpride;antipsychotics

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Melanocortin receptors

Most potent curated ligand interactions (18 total), top 18:

Ligand	Action	Affinity	Parameter
MCL0129	Antagonist	10.1	pKd
MBP10	Antagonist	10.0	pIC50
bremelanotide	Agonist	9.6	pKi
SHU9119	Antagonist	9.6	pKi
HS024	Antagonist	9.5	pKd
agouti-related protein	Inverse agonist	9.3	pIC50
[125I]SHU9119	Antagonist	9.2	pKd
[125I]NDP-MSH	Full agonist	8.9	pKd
THIQ	Full agonist	8.9	pIC50
MT-II	Full agonist	8.8	pKi
afamelanotide	Full agonist	8.8	pKi
setmelanotide	Agonist	8.68	pKi
HS014	Antagonist	8.5	pKd
RY764	Full agonist	8.1	pIC50
PG-901	Antagonist	8.1	pIC50
α-MSH	Full agonist	8.0	pKi
agouti	Inverse agonist	7.3	pKd
ACTH	Agonist	6.16	pKi

Binding affinities (BindingDB)

568 measured of 575 human assays (575 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-5-[(2,4-dichlorophenyl)methyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.055 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-5-[(3,4-dichlorophenyl)methyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.055 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-5-[[4-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.06 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-5-[(4-chlorophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.08 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-5-[(2,4-dimethylphenyl)methyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.085 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,18S)-18-[[(2S)-2-acetamidohexanoyl]amino]-N-[(2R)-1-amino-3-naphthalen-2-yl-1-oxopropan-2-yl]-5-benzyl-8-[3-(diaminomethylideneamino)propyl]-2-(1H-imidazol-5-ylmethyl)-3,6,9,15,19-pentaoxo-1,4,7,10,14-pentazacyclononadecane-11-carboxamide	KI	0.095 nM	US-9447148: Melanocortin-1 receptor-specific cyclic peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-5-[(4-methylphenyl)methyl]-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.145 nM	US-9040663: Melanocortin receptor-specific peptides
CAS_75921-69-6	KI	0.224 nM
alpha-MSH, [Nle4, D-Phe7]	KI	0.224 nM
1-[(3S)-3-({5-[2-(1,1-difluoroethyl)-1-	KI	0.23 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
2-(5-methoxy-2-methylphenyl)-1-[(3S)-	KI	0.23 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-5-[(4-fluorophenyl)methyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.25 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-5-[(4-methoxyphenyl)methyl]-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.25 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2R)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-8-[3-(diaminomethylideneamino)propyl]-5-[(3,4-difluorophenyl)methyl]-2-(1H-imidazol-5-ylmethyl)-11-(1H-indol-3-ylmethyl)-3,6,9,12,17,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.25 nM	US-9040663: Melanocortin receptor-specific peptides
1-[(3S)-3-({5-[2-(difluoromethyl)-1-	KI	0.25 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2R)-2-(3,5-dimethoxyphenyl)-1-[(3S)-	KI	0.28 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
1-[(3S)-3-({5-[5-(1,1-difluoroethyl)-1-	KI	0.29 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-5-[(3,4-difluorophenyl)methyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.3 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-[(2-chlorophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-2-(phenylmethoxymethyl)-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.3 nM	US-9040663: Melanocortin receptor-specific peptides
1-[(3S)-3-({5-[2-(difluoromethyl)-1-	KI	0.31 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
2-fluoro-1-[(3S)-3-{[6-methyl-5-(1-	KI	0.34 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-[(2-chlorophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-2-[(1R)-1-phenylmethoxyethyl]-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.35 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-5-benzyl-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,16,23-hexaoxo-1,4,7,10,13,17-hexazacyclotricosane-14-carboxamide	KI	0.4 nM	US-9458201: Melanocortin receptor-specific heptapeptides
(3S,6S,9R,12S,15S,23S)-12-(2-aminoethyl)-9-benzyl-15-[[(2S)-2-(cyclohexanecarbonylamino)-5-(diaminomethylideneamino)pentanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	KI	0.4 nM	US-9458201: Melanocortin receptor-specific heptapeptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-5-[(3-methylphenyl)methyl]-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.4 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-5-[(4-nitrophenyl)methyl]-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.45 nM	US-9040663: Melanocortin receptor-specific peptides
1-[(3S)-3-({5-[2-(1,1-difluoroethyl)-1-	KI	0.45 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
1-[(3S)-3-({5-[2-(difluoromethyl)-1-	KI	0.46 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2R)-1-[(3S)-3-({5-[5-(difluoromethyl)-1-	KI	0.46 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
1-[(3S)-3-({5-[2-(1,1-difluoroethyl)-1-	KI	0.48 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
2-(5-chloro-2-methoxypyridin-4-yl)-1-	KI	0.49 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-5-[(2-methylphenyl)methyl]-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.5 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-5-[(4-phenylphenyl)methyl]-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.5 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-[3-(carbamoylamino)propyl]-5-[(3-chlorophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.5 nM	US-9040663: Melanocortin receptor-specific peptides
(2R)-2-(5-chloro-2-methoxypyridin-4-	KI	0.51 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
2-(5-chloro-2-methoxypyridin-4-yl)-1-	KI	0.53 nM	US-20250129048: MELANOCORTIN 4 RECEPTOR ANTAGONISTS AND USES THEREOF
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-benzyl-8-[3-(diaminomethylideneamino)propyl]-2-(1H-imidazol-5-ylmethyl)-11-(1H-indol-3-ylmethyl)-3,6,9,12,17,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.6 nM	US-9458201: Melanocortin receptor-specific heptapeptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-5-[[2-(trifluoromethyl)phenyl]methyl]-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.6 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2R)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-[(3-chlorophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-2-(1H-imidazol-5-ylmethyl)-11-(1H-indol-3-ylmethyl)-3,6,9,12,17,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.6 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2R)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-[(4-cyanophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-2-(1H-imidazol-5-ylmethyl)-11-(1H-indol-3-ylmethyl)-3,6,9,12,17,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.6 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2R)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-8-[3-(diaminomethylideneamino)propyl]-5-[(4-fluorophenyl)methyl]-2-(1H-imidazol-5-ylmethyl)-11-(1H-indol-3-ylmethyl)-3,6,9,12,17,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.65 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-5-[(3,4,5-trifluorophenyl)methyl]-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.667 nM	US-9040663: Melanocortin receptor-specific peptides
(3S,11S,14S,17S,20R,23S,25R)-3-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-20-benzyl-17-[3-(diaminomethylideneamino)propyl]-14-(1H-indol-3-ylmethyl)-2,5,13,16,19,22-hexaoxo-25-phenylmethoxy-1,6,12,15,18,21-hexazabicyclo[21.3.0]hexacosane-11-carboxamide	KI	0.7 nM	US-9458201: Melanocortin receptor-specific heptapeptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-benzyl-2,8-bis[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.7 nM	US-9458201: Melanocortin receptor-specific heptapeptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-5-[(2-fluorophenyl)methyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.7 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-5-[(3-nitrophenyl)methyl]-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.7 nM	US-9040663: Melanocortin receptor-specific peptides
(2S,5R,8S,11S,14S,22S)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-2-(2-aminoethyl)-5-[(3-chlorophenyl)methyl]-8-[3-(diaminomethylideneamino)propyl]-11-(1H-indol-3-ylmethyl)-3,6,9,12,19,23-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-14-carboxamide	KI	0.75 nM	US-9040663: Melanocortin receptor-specific peptides

ChEMBL bioactivities

5399 potent at pChembl≥5 of 5623 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.82	Ki	0.01514	nM	CHEMBL4798971
10.82	Ki	0.015	nM	CHEMBL4798971
10.80	Ki	0.01585	nM	CHEMBL4794168
10.80	Ki	0.016	nM	CHEMBL4794168
10.78	Ki	0.0166	nM	CHEMBL4794121
10.77	Ki	0.017	nM	CHEMBL4794121
10.77	EC50	0.017	nM	AFAMELANOTIDE
10.74	EC50	0.018	nM	CHEMBL413212
10.72	EC50	0.019	nM	CHEMBL428615
10.71	Ki	0.0195	nM	CHEMBL4777048
10.70	Ki	0.02	nM	CHEMBL4777048
10.70	EC50	0.02	nM	AFAMELANOTIDE
10.68	Ki	0.021	nM	CHEMBL4788071
10.68	Ki	0.02089	nM	CHEMBL4793821
10.68	Ki	0.021	nM	CHEMBL4793821
10.67	Ki	0.02138	nM	CHEMBL4788071
10.62	EC50	0.024	nM	INTERMEDINE
10.59	Ki	0.0257	nM	CHEMBL4794990
10.59	Ki	0.026	nM	CHEMBL4794990
10.56	Ki	0.02754	nM	CHEMBL4791788
10.55	Ki	0.028	nM	CHEMBL4791788
10.55	Ki	0.02818	nM	CHEMBL3422426
10.54	Ki	0.029	nM	CHEMBL3422426
10.52	EC50	0.03	nM	CHEMBL4460053
10.47	Ki	0.03388	nM	MELATONAN
10.46	Ki	0.03467	nM	CHEMBL4800268
10.46	Ki	0.035	nM	CHEMBL4800268
10.40	EC50	0.04	nM	CHEMBL2070245
10.40	EC50	0.04	nM	MELATONAN
10.38	Ki	0.04169	nM	CHEMBL4776915
10.38	Ki	0.042	nM	CHEMBL4776915
10.36	Ki	0.044	nM	CHEMBL5194472
10.30	Ki	0.05	nM	CHEMBL339053
10.26	Ki	0.055	nM	CHEMBL3663320
10.26	Ki	0.055	nM	CHEMBL3663321
10.24	EC50	0.057	nM	MELATONAN
10.22	Ki	0.06	nM	CHEMBL442504
10.22	EC50	0.06	nM	CHEMBL415661
10.22	Ki	0.06	nM	CHEMBL3663336
10.22	EC50	0.06	nM	CHEMBL4569789
10.22	Ki	0.06	nM	CHEMBL5414451
10.22	IC50	0.06	nM	CHEMBL2096742
10.19	Ki	0.06457	nM	CHEMBL5414451
10.10	Ki	0.08	nM	CHEMBL2070251
10.10	Ki	0.08	nM	CHEMBL3663319
10.07	Ki	0.085	nM	CHEMBL3663337
10.06	IC50	0.087	nM	CHEMBL1161322
10.02	Ki	0.096	nM	CHEMBL385465
10.02	Ki	0.095	nM	CHEMBL3904232
10.00	IC50	0.1	nM	CHEMBL179836

PubChem BioAssay actives

3738 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-aminohexanoyl]amino]-9-benzyl-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxylic acid	108974: Intracellular level of cAMP in cells expressing the melanocortin 4 receptor	ec50	<0.0001	uM
(2S,5R,8S,11S,14S,23S)-23-(2-acetamidohexanoylamino)-5-benzyl-8-[3-(diaminomethylideneamino)propyl]-2-(1H-imidazol-5-ylmethyl)-11-(1H-indol-3-ylmethyl)-3,6,9,12,20,24-hexaoxo-1,4,7,10,13,19-hexazacyclotetracosane-14-carboxamide	1512890: Agonist activity at human FLAG-tagged MC4R expressed in HEK293 cells assessed as induction of intracellular cAMP accumulation after 2 hrs by AlphaScreen assay	ec50	<0.0001	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-5-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	108965: Effective concentration of peptide at 50% maximal cAMP generation	ec50	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-3-[(6-chloro-1H-indol-3-yl)methyl]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2R)-2-acetamido-5-aminopentanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-3-[(7-fluoro-1H-indol-3-yl)methyl]-12-(1H-imidazol-5-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-9-[(4-phenylphenyl)methyl]-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-3-[(5-fluoro-1H-indol-3-yl)methyl]-12-(1H-imidazol-5-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(6S,9S,12S,15R,18S,21S)-21-[[(2S)-2-acetamidohexanoyl]amino]-12-[3-(diaminomethylideneamino)propyl]-18-(1H-imidazol-5-ylmethyl)-9-(1H-indol-3-ylmethyl)-15-(naphthalen-2-ylmethyl)-8,11,14,17,20-pentaoxo-1,7,10,13,16,19,25,26-octazabicyclo[21.3.0]hexacosa-23,25-diene-6-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-3-[(7-chloro-1H-indol-3-yl)methyl]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(6S,9S,12S,15R,18S,21S)-21-[[(2S)-2-acetamidohexanoyl]amino]-12-[3-(diaminomethylideneamino)propyl]-18-(1H-imidazol-5-ylmethyl)-9-(1H-indol-3-ylmethyl)-15-(naphthalen-2-ylmethyl)-8,11,14,17,20-pentaoxo-1,7,10,13,16,19,24,25-octazabicyclo[21.2.1]hexacosa-23(26),24-diene-6-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-3-[(6-fluoro-1H-indol-3-yl)methyl]-12-(1H-imidazol-5-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-3-[(5-chloro-1H-indol-3-yl)methyl]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	1743780: Displacement of [125I]-[NIe,DPhe7]-alpha-MSH from human MC4R expressed in HEK293 cell membranes incubated for 120 mins	ki	<0.0001	uM
(2R)-2-(3,5-dimethoxyphenyl)-1-[(2S)-7-methyl-6-(1-methylpyrazol-4-yl)spiro[3,4-dihydro-1H-1,8-naphthyridine-2,3’-pyrrolidine]-1’-yl]propan-1-one	1885397: Displacement of [125I]-[Nle4-D-phe7]-alpha-MSH from to human MC4R expressed in CHO cells incubated for 2 hrs by liquid scintillation counting method	ki	<0.0001	uM
(2S)-2-acetamido-N-[(2R)-1-[[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-amino-1-oxo-3-sulfanylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]-5-(diaminomethylideneamino)pentanamide	1480175: Agonist activity at human MC4R expressed in high doxycyclin-treated HEK293 cell membranes assessed as increase in cAMP production after 15 mins by HTRF method	ec50	<0.0001	uM
(3R,6S,9R,12S,15S,23R)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-9-[(4-fluorophenyl)methyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	108970: Evaluated for agonist activity at cloned mammalian Melanocortin 4 receptor	ec50	<0.0001	uM
(3R,6S,9R,12S,15S,23R)-15-[[(2S)-2-acetamidohexanoyl]amino]-9-[(4-chlorophenyl)methyl]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	108970: Evaluated for agonist activity at cloned mammalian Melanocortin 4 receptor	ec50	<0.0001	uM
(3S)-N-[(2R)-1-[4-[2-[2-aminoethyl(methylsulfonyl)amino]phenyl]piperazin-1-yl]-3-(4-chlorophenyl)-1-oxopropan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide	246112: Effective concentration determined against melanocortin-4 receptor	ec50	0.0001	uM
Setmelanotide	1812567: Agonist activity at human melanocortin receptor 4 expressed in human T-REx-293 cells using high doxycycline assessed as stimulation of intracellular cAMP accumulation incubated for 45 mins by LANCE cAMP assay	ec50	0.0001	uM
(4S)-4-[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoylamino]-5-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1433975: Inhibition of human recombinant melanocortin 4 receptor expressed in CHO cells	ki	0.0001	uM
(4S)-4-[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoylamino]-5-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1512890: Agonist activity at human FLAG-tagged MC4R expressed in HEK293 cells assessed as induction of intracellular cAMP accumulation after 2 hrs by AlphaScreen assay	ec50	0.0001	uM
1-[3-[(1R,4S,7S,10S,13S,16R,19S,22S,25R,28S,31S,34S,37R,40S)-16,37-dibenzyl-4-[(2S)-butan-2-yl]-13-(3-carbamimidamidopropyl)-22-[(1R)-1-hydroxyethyl]-19,40-bis(1H-imidazol-4-ylmethyl)-10,31-bis(1H-indol-3-ylmethyl)-7,14,28-trimethyl-3,6,9,12,15,18,21,24,27,30,33,36,39,42-tetradecaoxo-44,45-dithia-2,5,8,11,14,17,20,23,26,29,32,35,38,41-tetradecazabicyclo[23.17.4]hexatetracontan-34-yl]propyl]guanidine	1812567: Agonist activity at human melanocortin receptor 4 expressed in human T-REx-293 cells using high doxycycline assessed as stimulation of intracellular cAMP accumulation incubated for 45 mins by LANCE cAMP assay	ec50	0.0001	uM
[(1S)-5-chloro-6-methyl-1-[2-(2-methyl-1,2,4-triazol-3-yl)propan-2-yl]spiro[1,2-dihydroindene-3,4’-piperidine]-1’-yl]-[(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(oxan-4-yl)amino]cyclopentyl]methanone	528112: Agonist activity at human MC4 receptor	ec50	0.0001	uM
(4R,7S,10S,13R,16S,19R)-13-benzyl-24-cyano-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-2-thia-5,8,11,14,17,20-hexazabicyclo[20.4.0]hexacosa-1(22),23,25-triene-4-carboxamide	1967900: Displacement of sCy5-MT-I from human MC4R stably expressed in human HEK293 cells incubated for 2 hrs by Cheng-Prusoff equation based FACS analysis	ki	0.0001	uM
(4R,7S,10S,13R,16S,19S)-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-24-[1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]triazol-4-yl]-2-thia-5,8,11,14,17,20-hexazabicyclo[20.4.0]hexacosa-1(22),23,25-triene-4-carboxamide	1967895: Agonist activity at human MC4R stably expressed in human Flp-In-293 cells assessed as cAMP accumulation incubated for 45 mins in presence of IBMX by Lance Ultra cAMP assay	ec50	0.0001	uM
(4R,7S,10S,13R,16S,19R)-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-24-nitro-6,9,12,15,18,21-hexaoxo-2-thia-5,8,11,14,17,20-hexazabicyclo[20.4.0]hexacosa-1(22),23,25-triene-4-carboxamide	1967900: Displacement of sCy5-MT-I from human MC4R stably expressed in human HEK293 cells incubated for 2 hrs by Cheng-Prusoff equation based FACS analysis	ki	0.0001	uM
(4R,7S,10S,13R,16S,19R)-24-amino-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-2-thia-5,8,11,14,17,20-hexazabicyclo[20.4.0]hexacosa-1(22),23,25-triene-4-carboxamide	1967900: Displacement of sCy5-MT-I from human MC4R stably expressed in human HEK293 cells incubated for 2 hrs by Cheng-Prusoff equation based FACS analysis	ki	0.0001	uM
(3R,6S,9S,12S,15S,23R)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	223527: Binding affinity against human melanocortin receptor 4 (hMC4R) (concentration of the peptide at 50% specific binding)	ki	0.0001	uM
(3R,6S,9R,12S,15S,23R)-15-acetamido-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	223527: Binding affinity against human melanocortin receptor 4 (hMC4R) (concentration of the peptide at 50% specific binding)	ki	0.0001	uM
N-[(2R)-3-(4-chlorophenyl)-1-[4-[2-[cyclopropylmethyl(methylsulfonyl)amino]phenyl]piperazin-1-yl]-1-oxopropan-2-yl]piperidine-4-carboxamide	108974: Intracellular level of cAMP in cells expressing the melanocortin 4 receptor	ec50	0.0001	uM
N-[2-[4-[(2S)-2-[(4-chlorophenyl)methyl]-4-[4-(3,3-dimethylbutanoyl)piperazin-1-yl]-4-oxobutanoyl]piperazin-1-yl]phenyl]-N-(cyclopropylmethyl)methanesulfonamide	109126: Inhibitory activity against [125I]NDP-alpha-MSH binding to the human melanocortin 4 receptor	ic50	0.0001	uM
(3R,11S,14S,17R,20S,23R)-3-[[(2R)-2-acetamidohexanoyl]amino]-17-[3-(diaminomethylideneamino)propyl]-14-(1H-indol-3-ylmethyl)-20-(naphthalen-2-ylmethyl)-2,5,13,16,19,22-hexaoxo-1,6,12,15,18,21-hexazabicyclo[21.3.0]hexacosane-11-carboxamide	107023: Binding affinity against human Melanocortin-4 receptor	ic50	0.0001	uM
3-[(4S,7R,10S,13S,16S,19R,22S)-22-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-carbamoyl-13-[(4-chlorophenyl)methyl]-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricos-19-yl]propanoic acid	239513: Inhibition of [125I]NDP-alpha-MSH binding to melanocortin-4 receptor expressed in HEK293 cells	ki	0.0001	uM
3-[(4S,7R,10S,13S,16S,19R,22S)-22-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-carbamoyl-10-[3-(diaminomethylideneamino)propyl]-13-[(4-fluorophenyl)methyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricos-19-yl]propanoic acid	246243: Agonist activity at human Melanocortin-4 receptor as peptide required for 50% maximal cAMP release (n > or =2)	ec50	0.0001	uM
3-[(4S,7R,10S,13S,16S,19R,22S)-22-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-6-aminohexanoyl]amino]-13-benzyl-4-carbamoyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricos-19-yl]propanoic acid	246243: Agonist activity at human Melanocortin-4 receptor as peptide required for 50% maximal cAMP release (n > or =2)	ec50	0.0001	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-5-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]pentanoic acid	1477002: Agonist activity at human MC4R expressed in HEK293 cells assessed as induction of intracellular cAMP accumulation after 3 mins	ec50	0.0002	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	108968: Effective concentration required for the biological activity against human Melanocortin 4 receptor	ec50	0.0002	uM
(2R)-2-(5-chloro-2-methoxy-4-pyridinyl)-1-[(2S)-7-methyl-6-(2-methyltetrazol-5-yl)spiro[3,4-dihydro-1H-1,8-naphthyridine-2,3’-pyrrolidine]-1’-yl]propan-1-one	1885397: Displacement of [125I]-[Nle4-D-phe7]-alpha-MSH from to human MC4R expressed in CHO cells incubated for 2 hrs by liquid scintillation counting method	ki	0.0002	uM
1-[3-[(1R,4S,7S,13S,16S,19R,22S,25S,28R,31S,34S,37S,40R,43S)-19,40-dibenzyl-16-(3-carbamimidamidopropyl)-25-[(1R)-1-hydroxyethyl]-22,43-bis(1H-imidazol-4-ylmethyl)-13,34-bis(1H-indol-3-ylmethyl)-4,17,31-trimethyl-3,6,12,15,18,21,24,27,30,33,36,39,42,45-tetradecaoxo-47,48-dithia-2,5,11,14,17,20,23,26,29,32,35,38,41,44-tetradecazatricyclo[26.17.4.07,11]nonatetracontan-37-yl]propyl]guanidine	1812567: Agonist activity at human melanocortin receptor 4 expressed in human T-REx-293 cells using high doxycycline assessed as stimulation of intracellular cAMP accumulation incubated for 45 mins by LANCE cAMP assay	ec50	0.0002	uM
1-[3-[(1R,4S,7S,13S,16S,19R,22S,25S,28R,31S,34S,37S,40R,43S)-19,40-dibenzyl-4-[(2S)-butan-2-yl]-16-(3-carbamimidamidopropyl)-25-[(1R)-1-hydroxyethyl]-22,43-bis(1H-imidazol-4-ylmethyl)-13,34-bis(1H-indol-3-ylmethyl)-17,31-dimethyl-3,6,12,15,18,21,24,27,30,33,36,39,42,45-tetradecaoxo-47,48-dithia-2,5,11,14,17,20,23,26,29,32,35,38,41,44-tetradecazatricyclo[26.17.4.07,11]nonatetracontan-37-yl]propyl]guanidine	1812567: Agonist activity at human melanocortin receptor 4 expressed in human T-REx-293 cells using high doxycycline assessed as stimulation of intracellular cAMP accumulation incubated for 45 mins by LANCE cAMP assay	ec50	0.0002	uM
(4R,7S,10S,13R,16S)-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-21-ethynyl-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-2-thia-5,8,11,14,17-pentazabicyclo[17.4.0]tricosa-1(19),20,22-triene-4-carboxamide	1967900: Displacement of sCy5-MT-I from human MC4R stably expressed in human HEK293 cells incubated for 2 hrs by Cheng-Prusoff equation based FACS analysis	ki	0.0002	uM
(4R,7S,10S,13R,16S,19R)-13-benzyl-24-carbamimidoyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-2-thia-5,8,11,14,17,20-hexazabicyclo[20.4.0]hexacosa-1(22),23,25-triene-4-carboxamide	1967900: Displacement of sCy5-MT-I from human MC4R stably expressed in human HEK293 cells incubated for 2 hrs by Cheng-Prusoff equation based FACS analysis	ki	0.0002	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2-amino-2-oxoethyl)amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	246243: Agonist activity at human Melanocortin-4 receptor as peptide required for 50% maximal cAMP release (n > or =2)	ec50	0.0002	uM
(3S,11R,14R,17S,20S,23S)-3-[[(2S)-2-acetamidohexanoyl]amino]-20-benzyl-17-[3-(diaminomethylideneamino)propyl]-14-(1H-indol-3-ylmethyl)-2,5,13,16,19,22-hexaoxo-1,6,12,15,18,21-hexazabicyclo[21.3.0]hexacosane-11-carboxamide	108976: Intracellular levels of cAMP in HEK 293 cells expressing human melanocortin 4 receptor (hMC4R)	ec50	0.0002	uM
(3R,6S,9R,12S,15S,23R)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-9-[(4-iodophenyl)methyl]-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	109272: Evaluated for partial agonistic activity at cloned mammalian Melanocortin 4 receptor	kd	0.0002	uM
(3S,6R,9R,12R,15R,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-9-[(4-iodophenyl)methyl]-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide	109273: pA2 against human melanocortin receptor, human Melanocortin 4 receptor	kd	0.0002	uM
(3R,11S,14S,17R,20S,23R)-3-[[(2R)-2-acetamidohexanoyl]amino]-17-[3-(diaminomethylideneamino)propyl]-22-hydroxy-14-(1H-indol-3-ylmethyl)-20-(naphthalen-2-ylmethyl)-2,5,13,16,19-pentaoxo-1,6,12,15,18,21-hexazabicyclo[21.3.0]hexacosane-11-carboxamide	107022: Binding affinity against human Melanocortin-4 receptor	ic50	0.0002	uM
(1R,4S,7R,10S,13S,21R,24R,29R)-21-[[(2R)-2-acetamidohexanoyl]amino]-7-[3-(diaminomethylideneamino)propyl]-10-(1H-indol-3-ylmethyl)-24,29-dimethyl-4-(naphthalen-2-ylmethyl)-2,5,8,11,19,22-hexaoxo-3,6,9,12,18,23-hexazatricyclo[21.7.0.024,29]triacontane-13-carboxamide	107022: Binding affinity against human Melanocortin-4 receptor	ic50	0.0002	uM
(4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[(2S)-2-[[(2S)-1-(carboxymethylamino)-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-3-carboxy-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-oxopentanoic acid	240058: Effective concentration against human melanocortin-4 receptor	ec50	0.0002	uM
(3S)-3-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(4S,7R,10S,13S,16S,19R,22S)-22-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-13-benzyl-19-(2-carboxyethyl)-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-4-ylmethyl)-7-(1H-indol-3-ylmethyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carbonyl]amino]-3-hydroxypropanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-6-aminohexanoyl]amino]-4-amino-4-oxobutanoic acid	246243: Agonist activity at human Melanocortin-4 receptor as peptide required for 50% maximal cAMP release (n > or =2)	ec50	0.0002	uM

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects methylation	3
bisphenol A	affects cotreatment, decreases methylation	1
MSH, 4-Nle-7-Phe-alpha-	increases activity	1
indole	affects binding	1
naphthalene	affects binding	1
2-palmitoylglycerol	increases expression	1
bisphenol S	increases methylation	1
LY2112688	affects binding, increases activity	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	increases expression	1
Estradiol	increases expression	1
Lead	affects expression	1
Dronabinol	decreases expression	1
Triclosan	decreases expression	1

ChEMBL screening assays

663 unique, capped per target: 364 binding, 293 functional, 6 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL826750	Binding	Ratio of EC50 of Melanocortin 4 receptor to that of Melanocortin 3 receptor	End-capping of the modified melanocortin tetrapeptide (p-Cl)Phe-D-Phe-Arg-Trp-NH2 as a route to hMC4R agonists. — Bioorg Med Chem Lett
CHEMBL825473	Functional	Selectivity for melanocortin 4 receptor compared to melanocortin 5 receptor in vitro	Melanocortin subtype-4 receptor agonists containing a piperazine core with substituted aryl sulfonamides. — Bioorg Med Chem Lett
CHEMBL4032183	ADMET	Displacement of [125I]-NDP-alpha-MSH from human MC4R expressed in HEK293 cells after 40 mins by gamma counting method	Design of MC1R Selective γ-MSH Analogues with Canonical Amino Acids Leads to Potency and Pigmentation. — J Med Chem

Cellosaurus cell lines

6 cell lines: 3 spontaneously immortalized cell line, 2 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0T5	ACTOne MC4R	Transformed cell line	Female
CVCL_H461	CHO-K1/MC4/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KV47	cAMP Hunter CHO-K1 MC4R Gs	Spontaneously immortalized cell line	Female
CVCL_LA70	PathHunter U2OS MC4R beta-arrestin	Cancer cell line	Female
CVCL_YK18	HEK293 MC4R HiTSeeker	Transformed cell line	Female
CVCL_ZK74	GeneBLAzer MC4R-CRE-bla CHO-K1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
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