ABSTRACT
Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having K(i) values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues.
Subject(s)
Benzylamines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Administration, Oral , Animals , Benzylamines/administration & dosage , Benzylamines/chemistry , Benzylamines/pharmacokinetics , Biological Availability , Cell Line , Humans , Mice , Piperazines/chemistryABSTRACT
Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.
Subject(s)
Benzylamines/pharmacology , Feeding Behavior/drug effects , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Satiety Response , Animals , Cell Line , Dose-Response Relationship, Drug , Humans , MiceABSTRACT
SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compound 12e and the quinolin-3-ylcarbonyl analogue 12l possessed K(i) values of 6.3 and 4.5 nM, respectively. Interestingly, 12e was a full agonist with an EC(50) value of 31 nM, and 12l was a weak partial agonist (IA=17%) and functioned as an antagonist (IC(50)=300 nM).
Subject(s)
Benzylamines/chemical synthesis , Benzylamines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Cell Line , Cyclic AMP/analysis , Dose-Response Relationship, Drug , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/genetics , Structure-Activity Relationship , Transfection , alpha-MSH/analysisABSTRACT
SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K(i) values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation ( approximately 15% of alpha-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of alpha-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC(50)=36 nM).
Subject(s)
Benzylamines/pharmacology , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Benzylamines/chemical synthesis , Humans , Molecular Structure , Piperazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.
