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Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.
The melanocyte-stimulating hormones, known collectively as MSH, also known as melanotropins or intermedins, are a family of peptide hormones and neuropeptides consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH) that are produced by cells in the pars intermedia of the anterior lobe of the pituitary gland.
Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women. Specifically it is used for low sexual desire which occurs before menopause and is not due to medical problems, psychiatric problems, or problems within the relationship. It is given by an injection just under the skin of the thigh or abdomen.
Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.
The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function.
Melanotan II is a synthetic analogue of the peptide hormone α-melanocyte-stimulating hormone (α-MSH) that stimulates melanogenesis and increases sexual arousal.
Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.
Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.
Melanocortin 3 receptor (MC3R) is a protein that in humans is encoded by the MC3R gene.
Melanocortin 5 receptor (MC5R) is a protein that in humans is encoded by the MC5R gene. It is located on the chromosome 18 in the human genome. When the MC5R was disrupted in transgenic mice, it induced disruption of their exocrine glands and resulted in decreased production of sebum.
The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:
THIQ is a drug used in scientific research, which is the first non-peptide agonist developed that is selective for the melanocortin receptor subtype MC4. In animal studies, THIQ stimulated sexual activity in rats, but with little effect on appetite or inflammation. This supports possible application of MC4 selective agonists for the treatment of sexual dysfunction in humans, although THIQ itself has poor oral bioavailability and a short duration of action so improved analogues will need to be developed.
The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein–coupled receptor that binds to a class of pituitary peptide hormones known as the melanocortins, which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH). It is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase in cells expressing this receptor. It is normally expressed in skin and melanocytes, and to a lesser degree in periaqueductal gray matter, astrocytes and leukocytes. In skin cancer, MC1R is highly expressed in melanomas but not carcinomas.
α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It is the most important of the melanocyte-stimulating hormones (MSHs) (also known as melanotropins) in stimulating melanogenesis, a process that in mammals (including humans) is responsible for pigmentation primarily of the hair and skin. It also plays a role in feeding behavior, energy homeostasis, sexual activity, and protection against ischemia and reperfusion injury.
Semax is a drug which is used mostly in Russia for a broad range of conditions but predominantly for its purported nootropic, neuroprotective, and neurorestorative properties. Semax has not been evaluated, approved for use, or marketed in most other countries.
Melanocortin 2 receptor accessory protein 2 is a protein that in humans is encoded by the MRAP2 gene. MRAP2 is a transmembrane accessory protein to a family of five receptors called the melanocortin receptors (MC1-5). Human genome sequencing analysis led to the discovery of MRAP2, Human MRAP2 gene is located in chromosome 6q14.3, a different chromosomal location from that of human MRAP which is a paralogy to MRAP2. MRAP2 is thought to be involved in regulating the expression of the melanocortin (MC1-5) and some non-melanocortin receptors such as ghrelin receptor (GHSR-1a), orexin (OX1R) receptor and prokineticin receptor (PKR-1).
Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.
Modimelanotide (INN) (code names AP-214, ABT-719, ZP-1480) is a melanocortinergic peptide drug derived from α-melanocyte-stimulating hormone (α-MSH) which was under development by, at different times, Action Pharma, Abbott Laboratories, AbbVie, and Zealand for the treatment of acute kidney injury. It acts as a non-selective melanocortin receptor agonist, with IC50 values of 2.9 nM, 1.9 nM, 3.7 nM, and 110 nM at the MC1, MC3, MC4, and MC5 receptors. Modimelanotide failed clinical trials for acute kidney injury despite showing efficacy in animal models, and development was not further pursued.
β-Melanocyte-stimulating hormone (β-MSH) is an endogenous peptide hormone and neuropeptide. It is a melanocortin, specifically, one of the three types of melanocyte-stimulating hormone (MSH), and is produced from proopiomelanocortin (POMC). It is an agonist of the MC1, MC3, MC4, and MC5 receptors.
γ-Melanocyte-stimulating hormone (γ-MSH) is an endogenous peptide hormone and neuropeptide. It is a melanocortin, specifically, one of the three types of melanocyte-stimulating hormone (MSH), and is produced from proopiomelanocortin (POMC). It is an agonist of the MC1, MC3, MC4, and MC5 receptors. It exists in three forms, γ1-MSH, γ2-MSH, and γ3-MSH.
References
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- ↑ Voisey J, Carroll L, van Daal A (October 2003). "Melanocortins and their receptors and antagonists". Current Drug Targets. 4 (7): 586–97. doi:10.2174/1389450033490858. PMID 14535656.
- ↑ Hadley ME, Dorr RT (April 2006). "Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization". Peptides. 27 (4): 921–30. doi:10.1016/j.peptides.2005.01.029. PMID 16412534.
- ↑ Dores RM (April 2009). "Adrenocorticotropic hormone, melanocyte-stimulating hormone, and the melanocortin receptors: revisiting the work of Robert Schwyzer: a thirty-year retrospective". Annals of the New York Academy of Sciences. 1163 (1): 93–100. doi:10.1111/j.1749-6632.2009.04434.x. PMID 19456331.
- ↑ Lam, B.Y.H., Williamson, A., Finer, S. et al. MC3R links nutritional state to childhood growth and the timing of puberty. Nature (2021). doi : 10.1038/s41586-021-04088-9
- ↑ Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S (2003). "Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene". N. Engl. J. Med. 348 (12): 1085–95. doi: 10.1056/NEJMoa022050 . PMID 12646665.
- ↑ Chai B, Pogozheva I, Lai Y, Li J, Neubig R, Mosberg H, Gantz I (2005). "Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors". Biochemistry. 44 (9): 3418–31. doi:10.1021/bi0478704. PMID 15736952.
- ↑ Pogozheva I, Chai B, Lomize A, Fong T, Weinberg D, Nargund R, Mulholland M, Gantz I, Mosberg H (2005). "Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists". Biochemistry. 44 (34): 11329–41. doi:10.1021/bi0501840. PMC 2532597 . PMID 16114870.
- ↑ Balse-Srinivasan P, Grieco P, Cai M, Trivedi D, Hruby VJ (November 2003). "Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues". Journal of Medicinal Chemistry. 46 (23): 4965–73. doi:10.1021/jm030119t. PMID 14584947.
- ↑ Wilson KR, Todorovic A, Proneth B, Haskell-Luevano C (2006). "Overview of endogenous and synthetic melanocortin peptides". Cellular and Molecular Biology (Noisy-le-Grand, France). 52 (2): 3–20. PMID 16914082.
- ↑ Hruby VJ, Cai M, Cain JP, Mayorov AV, Dedek MM, Trivedi D (2007). "Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor". Current Topics in Medicinal Chemistry. 7 (11): 1107–19. doi:10.2174/156802607780906645. PMC 2274922 . PMID 17584128.
- ↑ Mayorov AV, Cai M, Palmer ES, Dedek MM, Cain JP, Van Scoy AR, Tan B, Vagner J, Trivedi D, Hruby VJ (January 2008). "Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor". Journal of Medicinal Chemistry. 51 (2): 187–95. doi:10.1021/jm070461w. PMC 2587288 . PMID 18088090.
- ↑ Kadekaro AL, Kanto H, Kavanagh R, Abdel-Malek ZA (June 2003). "Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival". Annals of the New York Academy of Sciences. 994 (1): 359–65. doi:10.1111/j.1749-6632.2003.tb03200.x. PMID 12851336.
- ↑ King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007). "Melanocortin receptors, melanotropic peptides and penile erection". Current Topics in Medicinal Chemistry. 7 (11): 1098–1106. doi:10.2174/1568026610707011111. PMC 2694735 . PMID 17584130.
- ↑ Cragnolini AB, Schiöth HB, Scimonelli TN (June 2006). "Anxiety-like behavior induced by IL-1beta is modulated by alpha-MSH through central melanocortin-4 receptors". Peptides. 27 (6): 1451–6. doi:10.1016/j.peptides.2005.10.020. PMID 16325304.
- ↑ Catania A (July 2008). "Neuroprotective actions of melanocortins: a therapeutic opportunity". Trends in Neurosciences. 31 (7): 353–60. doi:10.1016/j.tins.2008.04.002. PMID 18550183.
- ↑ Lasaga M, Debeljuk L, Durand D, Scimonelli TN, Caruso C (October 2008). "Role of alpha-melanocyte stimulating hormone and melanocortin 4 receptor in brain inflammation". Peptides. 29 (10): 1825–35. doi:10.1016/j.peptides.2008.06.009. hdl: 11336/104816 . PMID 18625277.
- ↑ Gonzalez PV, Schiöth HB, Lasaga M, Scimonelli TN (March 2009). "Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors". Brain, Behavior, and Immunity. 23 (6): 817–22. doi:10.1016/j.bbi.2009.03.001. hdl: 11336/104814 . PMID 19275930.
- ↑ Chaki S, Oshida Y, Ogawa S, Funakoshi T, Shimazaki T, Okubo T, Nakazato A, Okuyama S (December 2005). "MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity". Pharmacology Biochemistry and Behavior. 82 (4): 621–6. doi:10.1016/j.pbb.2005.11.001. PMID 16337261.
- ↑ Chaki S, Hirota S, Funakoshi T, Suzuki Y, Suetake S, Okubo T, Ishii T, Nakazato A, Okuyama S (February 2003). "Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor". The Journal of Pharmacology and Experimental Therapeutics. 304 (2): 818–26. doi:10.1124/jpet.102.044826. PMID 12538838.