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Wednesday, August 6, 2025

Melanocortin receptor agonists


Definition

Melanocortin receptor agonists (MC receptor agonists) are a class of pharmacologic agents that activate melanocortin receptors (MCRs) — a group of G protein-coupled receptors (GPCRs) involved in the regulation of energy homeostasis, appetite, pigmentation, sexual function, adrenal steroidogenesis, and inflammation.

These drugs mimic the physiological actions of α-, β-, and γ-melanocyte-stimulating hormones (MSHs) and adrenocorticotropic hormone (ACTH) by binding to and activating specific MCR subtypes (MC1R to MC5R). Their role in pharmacotherapy is rapidly expanding, particularly in the fields of genetic obesity syndromes, sexual dysfunction, inflammatory diseases, and pigmentation disorders.

Melanocortin Receptors: Subtypes and Distribution

There are five known melanocortin receptors (MC1R–MC5R), each with specific tissue localization and functional roles:

ReceptorLocationFunction
MC1RMelanocytes, immune cellsSkin/hair pigmentation, immune modulation
MC2RAdrenal cortexCortisol synthesis (activated by ACTH only)
MC3RHypothalamus, CNS, gutEnergy balance, feeding behavior
MC4RHypothalamus, brainstemAppetite suppression, sexual behavior, energy homeostasis
MC5RExocrine glands, CNSExocrine secretion, sebaceous gland function


Each receptor subtype is a potential therapeutic target, and drugs in this class are often designed to selectively activate one or more of these subtypes depending on the disease being treated.

Mechanism of Action

Melanocortin receptor agonists exert their action through agonism of one or more MCRs. Upon binding, they initiate intracellular signaling cascades via Gs protein-coupled activation of adenylate cyclase, leading to increased cyclic AMP (cAMP) levels and downstream effects such as:

  • MC4R agonism → reduced appetite, enhanced energy expenditure

  • MC1R agonism → increased melanin production in melanocytes

  • MC2R agonism → stimulation of cortisol synthesis

  • MC3R agonism → regulation of metabolic and circadian rhythms

  • MC5R agonism → modulation of sebaceous gland activity

Some drugs act on multiple MCR subtypes, leading to pleiotropic effects (e.g., anti-inflammatory + metabolic).

Therapeutic Indications

  1. Genetic Obesity Syndromes

    • e.g., Pro-opiomelanocortin (POMC) deficiency, leptin receptor (LEPR) deficiency, Bardet-Biedl syndrome (BBS)

    • MC4R agonists restore appetite control and reduce hyperphagia

  2. Hypoactive Sexual Desire Disorder (HSDD)

    • MC4R activation improves sexual arousal pathways in CNS

  3. Erythropoietic Protoporphyria (EPP)

    • MC1R agonists increase eumelanin production, improving sun tolerance

  4. Inflammatory and Autoimmune Disorders (experimental)

    • MC1R, MC3R agonists modulate immune responses

  5. Melanogenesis and Pigmentation Disorders

    • Targeting MC1R in conditions like vitiligo and albinism (research)

Key Drugs in Class

1. Setmelanotide

  • Brand: Imcivree

  • Target: Potent MC4R agonist

  • Indications:

    • Chronic weight management in genetic obesity syndromes (POMC, PCSK1, LEPR, BBS)

  • Mechanism: Restores central melanocortin signaling to reduce appetite and body weight

  • Dose: Starting at 2 mg SC daily in adults, titrated to maintenance

  • Approval: FDA and EMA approved for specific rare genetic obesity disorders

  • Side Effects: Hyperpigmentation, injection site reactions, nausea, mood changes

  • Notes: Not for use in general obesity not caused by melanocortin pathway mutations

2. Bremelanotide

  • Brand: Vyleesi

  • Target: MC4R (primary), also weak MC1R agonist

  • Indications:

    • Premenopausal women with hypoactive sexual desire disorder (HSDD)

  • Mechanism: Enhances sexual desire through CNS activation of MC4R pathways

  • Dose: 1.75 mg SC as needed (max once per 24 hours, 8x/month)

  • Approval: FDA approved in 2019

  • Side Effects: Nausea, flushing, injection site reaction, transient ↑ BP

  • Contraindicated: Uncontrolled hypertension, known cardiovascular disease

3. Afamelanotide

  • Brand: Scenesse

  • Target: MC1R

  • Indications:

    • Erythropoietic protoporphyria (EPP) to reduce phototoxic reactions

  • Mechanism: Stimulates melanin production to enhance photoprotection

  • Dose: 16 mg SC implant every 2 months

  • Approval: EMA (2014), FDA (2019)

  • Side Effects: Hyperpigmentation, nausea, headache, fatigue

Pharmacokinetics

ParameterSetmelanotideBremelanotideAfamelanotide
RouteSubcutaneousSubcutaneous (on-demand)Subcutaneous implant
Onset of ActionDays to weeks~1 hourWithin days
Half-life~11 hours~2.5 hours~6 days
MetabolismProteolytic degradationRenal + hepatic pathwaysMetabolized in skin/tissues
ExcretionFeces + urineMostly renalNot fully characterized



Adverse Effects

AgentCommon Adverse Effects
SetmelanotideHyperpigmentation, headache, nausea, depression, injection site pain
BremelanotideNausea (40%), flushing, ↑ blood pressure, darkening of skin or gums
AfamelanotideImplant site reaction, nausea, headache, fatigue, darkened freckles


Rare but serious reactions:

  • Cardiovascular (especially with bremelanotide)

  • Mood changes (depression, suicidal ideation – monitor closely)

  • Elevated liver enzymes (rare)

Contraindications

  • Bremelanotide:

    • Uncontrolled hypertension

    • Cardiovascular disease

    • Pregnancy

  • Setmelanotide:

    • Not indicated for non-MC4R pathway obesity

    • Use caution in patients with psychiatric disorders

  • Afamelanotide:

    • Hypersensitivity to implant materials

    • Pigmented skin disorders (precaution)

Drug Interactions

  • Bremelanotide:

    • Delays gastric emptying; may reduce absorption of oral drugs

    • Avoid in patients taking hypotensives, due to transient pressor effect

  • Setmelanotide:

    • Limited data; may influence appetite-controlling pathways affected by other obesity drugs

  • Afamelanotide:

    • No significant drug-drug interactions reported

Monitoring Parameters

  • All agents:

    • Injection site reactions

    • Skin changes (hyperpigmentation)

    • Mood alterations (especially depression, suicidal ideation)

  • Setmelanotide:

    • Weight loss trajectory, waist circumference, appetite control, psychiatric symptoms

  • Bremelanotide:

    • Blood pressure and heart rate pre- and post-dose, especially in hypertensive patients

  • Afamelanotide:

    • Liver function tests, melanin levels, phototoxic response improvement

Clinical Applications Summary

IndicationDrugTarget ReceptorOutcome
Genetic obesity (POMC/LEPR)SetmelanotideMC4R↓ Appetite, sustained weight loss
Hypoactive sexual desire disorderBremelanotideMC4R (mostly)↑ Sexual desire and responsiveness
Erythropoietic protoporphyriaAfamelanotideMC1R↑ Melanin, ↓ Phototoxic reactions
Vitiligo, albinism (research)AfamelanotideMC1RSkin pigmentation restoration
Inflammatory disease (experimental)TBDMC1R, MC3RImmune modulation (preclinical evidence)



Special Populations

  • Pediatrics:

    • Setmelanotide approved for ages ≥6 with POMC, LEPR, or BBS syndromes

    • Afamelanotide and bremelanotide not approved for pediatric use

  • Pregnancy:

    • All agents classified with caution due to lack of sufficient safety data

    • Bremelanotide is contraindicated

  • Renal/Hepatic impairment:

    • Use with caution, especially with bremelanotide due to systemic effects

  • Elderly:

    • Limited data; monitor cardiovascular function closely with bremelanotide

Current Research and Pipeline

  1. MC1R Agonists for Vitiligo

    • Experimental topical and systemic agents showing promise in repigmentation

  2. MC4R Agonists in Common Obesity

    • Modified MC4R agonists are being investigated for non-genetic obesity

    • Balancing efficacy with reduced cardiovascular risk is a key challenge

  3. Melanocortin-Based Anti-Inflammatory Therapies

    • Potential use in rheumatoid arthritis, Crohn’s disease, and MS

    • Targeting MC1R and MC3R for immune modulation

  4. Dual or Multi-Receptor Agonists

    • Development of drugs that activate MC3R + MC4R or MC1R + MC5R for broader systemic benefits

  5. Peptide-Drug Conjugates and Depot Formulations

    • Sustained-release and long-acting MC agonists for chronic indications under development

Summary Table of Melanocortin Receptor Agonists

Drug NameBrandReceptorIndicationRouteStatus
SetmelanotideImcivreeMC4RGenetic obesity syndromesSubcutaneousFDA/EMA Approved
BremelanotideVyleesiMC4R > MC1RHypoactive sexual desire disorderSubcutaneousFDA Approved
AfamelanotideScenesseMC1RErythropoietic protoporphyriaImplantFDA/EMA Approved





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