T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist.

Abstract Through the screening of our in-house chemical compound library, we found a novel melanin-concentrating hormone (MCH) receptor antagonist, T-226296, a (−) enantiomer of N -[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-fluoro[1,1′-biphenyl]-4-carboxamide. T-226296 exhibited high affinity for cloned human and rat MCH receptors (SLC-1) in receptor binding assays (IC 50 =5.5±0.12 nM for human SLC-1; 8.6±0.32 nM for rat SLC-1). T-226296 had high selectivity over other receptors, including the second subtype of the MCH receptor, SLT (MCH2), transporters and ion channels. In Chinese hamster ovary (CHO) cells expressing human SLC-1, T-226296 reversed the MCH-mediated inhibition of forskolin-stimulated cAMP accumulation, inhibited MCH-induced intracellular Ca 2+ increase, and also inhibited MCH-stimulated arachidonic acid release. In rats, oral administration of T-226296 (30 mg/kg) almost completely suppressed the food intake induced by intracerebroventricular injection of MCH. These results clearly indicate that T-226296 is a novel, orally active and selective MCH receptor antagonist that will be promising for further exploring the physiology and pathophysiology of MCH–SLC-1 signaling.