Melanocortin 4 receptor
Melanocortin 4 receptor is a protein that in humans is encoded by the MC4R gene. It encodes the MC4 protein, a G protein-coupled receptor that binds -melanocyte stimulating hormone (-MSH). In murine models MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.
In 2008, MC4R mutations were reported to be associated with inherited human obesity. They were found in heterozygotes, suggesting an autosomal dominant inheritance pattern. However, based on other research and observations, these mutations seem to have an incomplete penetrance and some degree of codominance. It has a prevalence of 1.02.5% in people with body mass indices greater than 30, making it the most commonly known genetic defect predisposing people to obesity.

# Clinical significance
In 2009, two very large genome-wide association studies of body mass index (BMI) confirmed the association of variants about 150 kilobases downstream of the MC4R gene with insulin resistance, obesity, and other anthropometric traits. MC4R may also have clinical utility as a biomarker for predicting individual susceptibility to drug-induced adverse effects causing weight gain and related metabolic abnormalities. Another GWAS performed in 2012 identified twenty SNPs located ~190 Kb downstream of MC4R in association with severe antipsychotic-induced weight gain. This locus overlapped with the region previously identified in the 2009 studies. The rs489693 polymorphism, in particular, sustained a statistically robust signal across three replication cohorts and demonstrated consistent recessive effects. This finding was replicated again by another research group in the following year. In accordance with the above, MC4 receptor agonists have garnered interest as potential treatments for obesity and insulin resistance, while MC4 receptor antagonists have attracted interest as potential treatments for cachexia.
MC4 receptor agonists like bremelanotide (PT-141), PL-6983, and PF-00446687 are under investigation as powerful potential treatments for both female and male sexual dysfunction, including hypoactive sexual desire disorder and erectile dysfunction. Bremelanotide and melanotan II are already used for sexual enhancement by the general population via their accessibility due to online drug vendors. The non-selective melanocortin receptor agonist afamelanotide (NDP--MSH) has been found to induce brain-derived neurotrophic factor (BDNF) expression in the rodent brain via activation of the MC4 receptor and mediate "intense" neurogenesis and cognitive recovery in an animal model of Alzheimer's disease. MC4 receptor antagonists produce pronounced antidepressant- and anxiolytic-like effects in animal models of depression and anxiety. And agonists of the MC4 receptor such as melanotan II and PF-00446687, via activation of the central oxytocin system, have been found to promote pair bond formation in prairie voles and, due to these prosocial effects, have been suggested as possible treatments for social deficits in autism spectrum disorders and schizophrenia.

# Interactions
The MC4 receptor has been shown to interact with proopiomelanocortin (POMC). POMC is a precursor peptide pro-hormone which is cleaved into several other peptide hormones. All of the endogenous ligands of MC4 are produced by cleaving this one precursor peptide. These endogenous agonists include -MSH, -MSH, -MSH, and ACTH.

# Ligands

## Agonists

### Non-selective
- -MSH
- -MSH
- -MSH
- ACTH
- Afamelanotide
- Bremelanotide
- Melanotan II
- Modimelanotide
- Setmelanotide

### Selective
- AZD2820
- LY-2112688
- MK-0493
- PF-00446687
- PG-931
- PL-6983
- Ro 27-3225  also some activity at MC1
- THIQ

## Antagonists

### Non-selective
- Agouti-related peptide
- Agouti signalling peptide
- SHU-8914
- SHU-9005
- SHU-9119

### Selective
- HS-014
- HS-024
- JKC-363
- MCL-0020
- MCL-0042  also a serotonin reuptake inhibitor
- MCL-0129
- ML-00253764
- MPB-10

## Unknown
- Semax