Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist.

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.

Activation of melanocortin MC(4) receptors increases erectile activity in rats ex copula.

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.

Comparison of Cardiovascular Parameters and/or Serum Chemistry and Hematology Profiles in Conscious and Anesthetized Rhesus Monkeys (Macaca mulatta).

The rhesus monkey is often used in pre-clinical research, and such studies frequently involve a variety of anesthetic conditions. Therefore, it is important to determine baseline physiologic blood chemistry and cardiovascular parameters in anesthetized animals to facilitate appropriate comparisons. The present study compares the cardiovascular parameters, hematology, serum chemistry, and blood gas levels of rhesus monkeys anesthetized with pentobarbital, isoflurane, ketamine, and propofol. Hematology, serum chemistry, and blood gas levels were unaffected by the four anesthetic regimens. However, because of its formulation, propofol is inappropriate for use in animals in which changes in tryglycerides will be evaluated. Compared to those in conscious, unrestrained monkeys, heart rates were higher in anesthetized animals, but the rates of anesthetized animals were similar regardless of anesthetic agent used. In contrast, mean arterial blood pressure was lower in animals anesthetized with pentobarbital, propofol, or isoflurane than in the conscious monkeys. However, mean arterial pressure of ketamine-anesthetized monkeys was similar to that of the conscious monkeys.