Awful narrow window between ecstasy and barfing? None at all for many subjects? This molecule is (I believe) a non-selective MR agonist. I'm not close enough to the project any longer, but the old hope was that a receptor subtype-selective molecule would handle ED with little or no barfing. Merck and others have MC4 projects re. obesity, and any such program will have a tangent dealing with ED, it would seem?
If I remember correctly, Biotech Jim was asking about this project once. He would know this stuff much better than me.
To get an idea of how widely the molecule is being used in experimental models, try a PubMed search using "MTII melanocortin". Here are a couple of abstracts that I found after searching for a whole thirty seconds (just posting random stuff which could be of interest..... for example, has anyone asked the company about taste issues?).......
Eur J Pharmacol. 2002 Nov 1;454(1):71-9.
Activation of melanocortin MC(4) receptors increases erectile activity in rats ex copula.
Martin WJ, McGowan E, Cashen DE, Gantert LT, Drisko JE, Hom GJ, Nargund R, Sebhat I, Howard AD, Van der Ploeg LH, MacIntyre DE.
Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. william_martin@merck.com
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.
Int J Obes Relat Metab Disord. 2003 May;27(5):550-6.
Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII.
Benoit SC, Sheldon RJ, Air EL, Messerschmidt P, Wilmer KA, Hodge KM, Jones MB, Eckstein DM, McOsker CC, Woods SC, Seeley RJ.
Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, OH 5267, USA. stephen.benoit@uc.edu
BACKGROUND: The synthetic melanocortin (MC) agonist, melanotan-II (MTII), reduces food intake and body weight for hours to days after administration. One early report on the effect of MTII suggested that part of its anorexic action may be mediated by aversive consequences. In that experiment, MTII was found to support a mild conditioned taste aversion (CTA). OBJECTIVE: The present experiments replicate and extend those findings in two additional CTA paradigms to further characterize the aversive effects of MTII in rats. METHODS: Experiment 1 simultaneously assessed the ability of MTII to support CTA and reduce food intake, using a small oral infusion of a novel taste as the conditioned stimulus. Experiment 2 assessed the aversive consequences of chronic MTII administration. To accomplish this, we paired implantation of lithium chloride (LiCl)-, MTII- or saline-containing osmotic minipumps with a constantly available novel flavor. After 7 days, rats received a choice test between the minipump-paired flavor and a previously available neutral flavor. RESULTS: Rats with saline minipumps exhibited no preference for either flavor. By contrast, rats in both the LiCl and MTII minipump groups significantly preferred the neutral flavor, indicating the development of a CTA. Additionally, CTA produced by administration of MTII was found to be more resistant to extinction than that produced by LiCl. CONCLUSIONS: The reduction in food intake caused by MTII is accompanied by aversive consequences regardless of route of administration. These results present difficulties for the development of MCs-based therapies for obesity. |
