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Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction

Key Points

  • The central and peripheral melanocortin system has multifaceted roles in the control of body-weight homeostasis, sexual behaviour, and autonomic and cardiovascular functions, and so targeting this pathway has potential for the treatment of multiple clinical disorders.

  • Melanocortin peptides are derived from pro-opiomelanocortin (POMC) and act as agonists on melanocortin receptors, of which the MC3 and MC4 subtypes are primarily involved in regulations of body-weight homeostasis, sexual behaviour, autonomic and cardiovascular functions.

  • POMC-containing neurons of the arcuate (infundibular) nucleus of the hypothalamus and in the brainstem are targets for peripheral satiety signals and project to many areas of the central nervous system. Their roles in the control of complex feeding behaviour are examined.

  • Agouti-related peptide (AgRP) is a small protein factor that is part of the melanocortin system and acts as an inverse agonist on the MC3 and MC4 receptors.

  • AgRP co-exists with neuropeptide Y (NPY) in neurons originating from the arcuate nucleus and are involved in interlinked control with the central POMC neurons, and with factors such as cocaine and amphetamine regulated transcript (CART), dopamine, leptin and insulin; their dysregulations may lead to adipocity and the metabolic syndrome.

  • Mutations exist in POMC, AgRP and the MC3 and MC4 receptors that seem to have causative roles in anorexia and obesity.

  • The central melanocortin system has a key role in the regulation of male and female sexual behaviour. The role of MC3 and MC4 receptors and the relation of the central melanocortin system with the central oxytocinergic system in control of sexual behaviour is discussed.

  • Stimulation of central MC4 receptors causes activation of the sympathetic system leading to rises in blood pressure, while γ-melanocyte-stimulating hormone (γ-MSH) released from the pituitary by acting on MC3 receptors causes blood-pressure reduction by stimulation of natriuresis in the kidneys.

  • We discuss the structural and physicochemical basis for the interaction of ligands with melanocortin receptors, and give an overview of the currently available peptide and non-peptide-based compounds with activity on MC3 and MC4 receptors.

  • Of the melanocortin receptor-targeted compounds, only bremelanotide, an MC4 agonist, has entered into clinical trials. It has shown clinical benefit in Phase II trials for erectile dysfunction and female sexual dysfunction, although reports of exacerbation of high blood pressure in some subjects means that further trials are on hold.

  • There are several merits and problems of such compounds for the treatment of obesity, the metabolic syndrome, anorexia and cachexia, and sexual dysfunction; a major obstacle in the development of MC4 agonists is side effects that lead to increased blood pressure. Mixed MC3/MC4 receptor agonists could overcome this problem.

Abstract

The melanocortin system has multifaceted roles in the control of body weight homeostasis, sexual behaviour and autonomic functions, and so targeting this pathway has immense promise for drug discovery across multiple therapeutic areas. In this Review, we first outline the physiological roles of the melanocortin system, then discuss the potential of targeting melanocortin receptors by using MC3 and MC4 agonists for treating weight disorders and sexual dysfunction, and MC4 antagonists to treat anorectic and cachectic conditions. Given the complexity of the melanocortin system, we also highlight the challenges and opportunities for future drug discovery in this area.

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Figure 1: The melanocortin (MC) system and its involvement in the regulation of body energy homeostasis.
Figure 2: Melanocortin-mediated cardiovascular control.
Figure 3: MC3 and MC4 receptor active peptides.
Figure 4: Derivatives of THIQ can be divided into structural families.
Figure 5: Examples of non-THIQ related compounds with melanocortin receptor activity.

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Acknowledgements

We are indebted to Dr P. Prusis and Dr A. Rinken for valuable comments on the manuscript. We are also indebted to Dr M. Lapinsh for providing the draft to figure 5. Support of research reported herein was obtained from the Swedish Research Council (04X-05957).

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Correspondence to Felikss Mutulis.

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Competing interests

J.E.S.W. holds a grant from the Swedish Research Council for studies on melanocortin receptors; holds shares in Genetta Soft AB, a Swedish company devoted to bioinformatics software; and is author of patents related to melancocortin receptors. F.M. has no competing financial interests.

Supplementary information

Supplementary information S1 (Box)

Amino acids delineating MC4 receptor selectivity of organic amines. (PDF 418 kb)

Supplementary information S2 (Box)

Possible mechanism of ligand binding to MC4 receptor dimers. (PDF 175 kb)

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DATABASES

OMIM

Anorexia nervosa

obesity

type 2 diabetes

IUPHAR Receptor Database

MC1

MC2

MC3

MC4

MC5

Glossary

Inverse agonist

An agent that binds to the same receptor binding site as an agonist for that receptor but exerts the opposite pharmacological effect. Inverse agonists reverse constitutive receptor activity, thereby decreasing signalling below basal levels.

Leptin

Leptin is a 16 kDa protein hormone that has a key role in regulating energy intake and energy expenditure. It is produced by adipose tissue and interacts with leptin receptors in the central nervous system.

Anorexia and cachexia

Anorexia and cachexia are common in old age and associated with many severe diseases, including anorexia nervosa, a distinct psychiatric condition with an unknown aetiology.

Afferent neurons

Afferent neurons are neurons that convey information from tissues and organs into the central nervous system.

Sympathetic neural chain

The paravertebral ganglionic chain is located just anterior and lateral to the spinal cord and is part of the sympathetic nervous system.

Salt-sensitive hypertension

Hypertension inducible by the excessive intake of sodium.

Natriuresis

Excretion of excessive amounts of sodium in the urine.

Lordotic sexual behaviour

Sexual behaviour of a female mammal, such as rats or mice, consisting of a ventral arching of the spine.

Frameshift

Insertions or deletions of one or more nucleotides in DNA that cause a shift in its reading frame (frameshift). A significant alteration in the gene product results.

Haploinsufficiency

A state in which a diploid organism has a single functional copy of a gene (with the other copy inactivated by mutation). The single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state.

Bioluminescence resonance energy transfer

A technology that can be used to monitor protein–protein interactions. A bioluminescent luciferase-labelled molecule is used to produce a photon emission, which excites a fluorophore-labelled molecule if the two molecules are in close proximity.

Fluorescence resonance energy transfer

A technology, similar to bioluminescence resonance energy transfer, used to monitor protein–protein interactions. External light is used to excite a fluorophore-labelled molecule, which then produces a photon emission, which excites a second fluorophore-labelled molecule if the two molecules are in close proximity.

Arrestin pathway

A biochemical pathway that regulates the activity of G-protein-coupled receptors (GPCRs) wherein GPCR kinases phosphorylate the C terminal tail of the receptor, which is followed by arrestin binding, leading to a desensitization of signalling.

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Wikberg, J., Mutulis, F. Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov 7, 307–323 (2008). https://doi.org/10.1038/nrd2331

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