What role does Milanocortin play in sexual function?

Melanocortin's Role in Sexual Function

Melanocortins act centrally through melanocortin-4 receptors (MC4R) in the hypothalamus and other brain regions to initiate penile erection and enhance sexual arousal, representing a fundamentally different mechanism than peripheral vascular therapies like PDE5 inhibitors. 1, 2

Mechanism of Action

Central Nervous System Pathway

• Melanocortin peptides derived from pro-opiomelanocortin (POMC) activate melanocortin receptors in the CNS, particularly MC3R and MC4R subtypes, to modulate erectile and sexual function 1, 2
• The MC4R subtype has emerged as the principal effector of melanocortin-induced erections, though MC3R's role remains incompletely understood 2
• These agents work through hypothalamic, brainstem, and potentially spinal pathways, possibly interacting with oxytocinergic systems 2

Key Distinction from Current Therapies

• Unlike PDE5 inhibitors that target end-organ vascular tissue peripherally, melanocortin agonists provide centrally-mediated effects on sexual function 2, 3
• This central mechanism addresses both erectile function and sexual desire/arousal, not just the mechanical aspects of erection 3

Clinical Evidence in Humans

Male Sexual Function

• Synthetic melanocortin agonists (melanotan II, bremelanotide/PT-141) have demonstrated proerectile effects in clinical trials 1, 4
• A selective small-molecule MC4R agonist (compound 40a) showed efficacy similar to sildenafil at 200 mg dosing in a pilot study of male erectile dysfunction 5
• Bremelanotide reached Phase II clinical trials and was well-tolerated without the hypotension associated with PDE5 inhibitors 3

Female Sexual Function

• Melanocortin agonists evoke pre-copulatory behaviors analogous to sexual arousal in animal models, with preliminary clinical data suggesting benefit for sexual desire and arousal in women 3
• This represents a potential treatment for female arousal and orgasmic disorders, addressing an unmet medical need 4, 3

Clinical Implications

Therapeutic Potential

• Melanocortin receptor manipulation may provide an alternative approach for erectile dysfunction when peripheral vascular therapies are contraindicated or ineffective 2
• The centrally-mediated activity addresses decreased sexual motivation and loss of libido in addition to erectile mechanics 2
• These agents may be particularly valuable for patients who cannot use nitrates (a contraindication for PDE5 inhibitors) 3

Current Development Status

• While bremelanotide advanced to Phase II trials, no melanocortin-based therapies are currently FDA-approved for sexual dysfunction 4, 3
• The receptor subtypes, pathways, and mechanisms mediating proerectile effects require further elucidation 1