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The lack of specific pharmacological tools has impeded the evaluation of the role of each melanocortin receptor (MCR) subtype in the myriad physiological effects of melanocortins. 154N-5 is an octapeptide (MFRdWFKPV-NH2) that was first identified as an MC1R antagonist in Xenopus melanophores [J. Biol. Chem. 269 (1994) 29846]. In this manuscript, we show that 154N-5 is a specific agonist for human and murine MC1R. The peptide has negligible activity at MC3R and MC4R and is 25-fold less potent and a weak agonist at MC5R. 154N-5 was tested in both a cellular and an animal model of tumor necrosis factor-α (TNF-α) secretion. The inhibitory efficacy of 154N-5 on TNF-α secretion in both models was similar to the nonselective agonist NDP-α-melanocyte stimulating hormone (NDP-αMSH), thus, we conclude that inhibition of TNF-α secretion by melanocortin peptides is mediated by MC1R. 154N-5 is a valuable new tool for the evaluation of specific contribution of MC1R agonism to physiological and pathological processes. [Copyright &y& Elsevier]

Abstract: Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro-[1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-[1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119. [Copyright &y& Elsevier]

Abstract: The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure–activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity. [Copyright &y& Elsevier]

Abstract: Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented. [Copyright &y& Elsevier]

Demonstrates that the orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. Cloning of GPR40; Activation of hGPR40 in HEK293 cells; Potency of the saturated fatty acids; Expression of GPR40 in human brain.

Identifies the acetate anion as an agonist of human G protein-coupled receptor 43 (GPR43) during routine ligand bank screening in yeast. Functions of GPR41 and GPR43; Activation of the receptors by propionate and other short chain carboxylic acids; Expression of GPR41 primarily in adipose tissue; Localization of GPR43 in immune cells.

Cites the molecular identification of high and low affinity receptors for nicotinic acid. Use of niconitic acid for the treatment of dyslipidemia; Normalization of cardiovascular risk factors; Mechanism of action of nicotinic acid.