ABSTRACT
A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
Subject(s)
Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Piperazines/pharmacology , Piperazines/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Biological Availability , Diet , Disease Models, Animal , Dogs , Drug Design , Drug Evaluation, Preclinical , Eating/drug effects , Male , Molecular Conformation , Piperazines/chemistry , Rats , StereoisomerismABSTRACT
A wide range of experimental evidence implicates a critical role for melanocortin signaling in the control of food intake and body adiposity. Melanocortin receptor agonists such as MT-II potently reduce food intake and body weight, making such agonists potential therapeutics for obesity. The critical concept addressed by the present experiments is whether the homeostatic effects of melanocortin agonists directly regulate food intake or whether the effects on food intake are secondary, with the primary effects being the regulation of body weight and adiposity. To investigate this, we compared the effect of various doses of MT-II given via osmotic minipump for 28 d to alter food intake, body weight, and body fat in dietary-induced obese rats. In addition, before the implantation of the minipump, dietary-induced obese rats were weight reduced by differing amounts using varying levels of food restriction. The results show that in food-restricted rats, MT-II-treated rats consume significantly more calories than those receiving MT-II after ad libitum access to food. More importantly, regardless of the widely differing levels of body fat among the different dietary treatments employed, body fat at the end of the study was determined exclusively by the dose of MT-II, with MT-II-treated rats having less body fat than vehicle-treated rats. These experiments support the hypothesis that melanocortin signaling primarily regulates total body adiposity and that food intake is adjusted as necessary to achieve a specific level of body adiposity.
