title: Activation of melanocortin MC(4) receptors increases erectile activity in rats ex copula.
abstract: Melanocortin peptide agonists, alpha-melanocyte stimulating hormone (alpha-MSH) and melanotan-II, stimulate erectile activity in a variety of species, including man. Since neither peptide discriminates amongst melanocortin receptors, it is not clear which subtype mediates these pro-erectile effects. Here, we present data that melanocortin-induced erectogenesis is mediated by melanocortin MC(4) receptors. Systemic administration of a melanocortin MC(4) receptor agonist (N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1ylmethyl)piperidin-1-yl]-2-oxoethylamine; THIQ) with high selectivity over other melanocortin receptors enhanced intracavernosal pressure and stimulated erectile activity in rats ex copula. THIQ dose-dependently (1-5 mg/kg, i.v.) increased the total number of erections, to an extent comparable or greater than that produced by apomorphine (0.025 mg/kg, s.c.). Central administration of THIQ (20 microg, intracerebroventricular (i.c.v.)) increased the number of reflexive penile erections; whereas administration of both a nonselective endogenous melanocortin MC(4) receptor antagonist (agouti-related protein (AgRP), 5.5. microg, i.c.v.) and a melanocortin MC(4) receptor preferring antagonist (MPB10, 1 mg/kg, i.v.) blocked THIQ-induced erectogenesis. These pro-erectile effects were also attenuated by systemic or central administration of an oxytocin antagonist (L-368899, 1 mg/kg, i.v.). Thus, melanocortin MC(4) receptor activation is sufficient for erectogenesis and these effects may involve oxytocinergic pathways.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. william_martin@merck.com
authors.forename: William J
authors.initials: WJ
authors.lastname: Martin
authors.forename: Erin
authors.initials: E
authors.lastname: McGowan
authors.forename: Doreen E
authors.initials: DE
authors.lastname: Cashen
authors.forename: Liza T
authors.initials: LT
authors.lastname: Gantert
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Drisko
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Hom
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.forename: Iyassu
authors.initials: I
authors.lastname: Sebhat
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Lex H T
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: D Euan
authors.initials: DE
authors.lastname: MacIntyre
mesh_terms: D054369:Agouti-Related Protein; D000818:Animals; D001667:Binding, Competitive; D001892:Camphanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists* / Q000037:antagonists & inhibitors; D044005:Tetrahydroisoquinolines; D014230:Triazoles / Q000494:pharmacology
chemical_list: D054369:Agouti-Related Protein; D001892:Camphanes; D007546:Isoquinolines; C438866:MBP10 peptide; C467221:N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044005:Tetrahydroisoquinolines; D014230:Triazoles; C411703:agouti-related protein-(83-132); C086206:L 368899