Melanocortin receptor MCR agonists

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Presently there are five MCRs identified and all five are activated by adrenocorticotropin hormone (ACTH) and four out of five, except MC2R, by alpha-melanocyte stimulating hormone (a-MSH) [1]. Of the five MCRs only two (MC3R and MC4R) are expressed in cerebral regions known to be involved in the modulation of erectile function. The origin of both a-MSH and ACTH is the pro-opiomelanocortin (POMC) gene, and the biologic effects of these two hormones are mediated via activation of one or more of the five MCRs. All five MCRs use cAMP as the second neurotransmitter mediating the final biologic (physiologic) effects upon their activation.

Melanotan II and its active metabolite PT-141 (Bremelanotide), are cyclic peptide analogues of a-MSH, targeting four of the five MCRs (not MC2R), which have been under investigation for nearly 10 years for their usefulness in the management of ED [2]. Following the first research studies Melanotan II was investigated both as subcutaneous injection and as intranasal spray [3,5].

Recently the results with the intranasal melanocortin receptor agonist PT-141 in an at home, multi-center, double-blind, placebo-controlled parallel-arm study in 271 sildenafil-responsive patients were reported, with improved erections in 66-67% with the 10-20mg dose [5]. As shown in Fig. 9.1 there was no dose-dependent efficacy between 10 and 20 mg. In two further Rigiscan studies with a subcutaneous (s.c.) application of PT-141 in doses between four and 10 mg, efficacy was reported even in a small group of patients (n = 25) with a history of inadequate response to 100 mg sildenafil and an IIEF-EF-score <17 [4]. A first response was seen approximately 37 min after the 10 mg dose. Mean duration of efficacy (definition: >60% penile base rigidity) was 41 min for the 6mg s.c. dose [4], whereas in another study the mean duration of efficacy after intranasal PT-141 was 26


GAQ -improvementof erection

Placebo 5mg PT-141 10mg PT-141 15mg PT-141 20mg PT-141

Fig. 9.1 At home efficacy of PT-141, an intranasal MCR-agonist, in 271 sildenafil-responsive patients [5].

min (6mg dose) and 54min (20mg dose), respectively, compared to 18.5 min in patients receiving placebo [3]. Co-administration of low doses of intranasal PT-141 (7.5mg) and sildenafil (25mg) in men suffering from ED resulted in an enhanced erectile response [6].

A major problem with this new MCR agonist may be its side effect profile, with nausea rates up to 36% after 6mg s.c and 17% after intranasal application [3,4]. Further drug related side effects >5% were headache (up to 27%), flushing (up to 17%) vomiting (up to 9%), back-pain (up to 9%), muscle cramps (up tp 9%), and fatigue (up to 8%).

There is no doubt that this completely new approach with MCR agonists seems to be promising in terms of efficacy, but at present there are some uncertainties regarding their side effect profile.

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