title: 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 (IC50=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 Ca2+ 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.
authors.affiliation: Discovery Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Wadai 10, Ibaraki 300-4293, Tsukuba, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Takekawa
authors.forename: Asano
authors.initials: A
authors.lastname: Asami
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
authors.forename: Kaneyoshi
authors.initials: K
authors.lastname: Kato
authors.forename: Yukio
authors.initials: Y
authors.lastname: Shimomura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
authors.forename: Hitomi
authors.initials: H
authors.lastname: Murakoshi
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Osamu
authors.initials: O
authors.lastname: Nishimura
authors.forename: Masahiko
authors.initials: M
authors.lastname: Fujino
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007028:Hypothalamic Hormones / Q000737:chemistry / Q000494:pharmacology; D007276:Injections, Intraventricular; D007457:Iodine Radioisotopes; D008297:Male; D008543:Melanins / Q000737:chemistry / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D010907:Pituitary Hormones / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D007028:Hypothalamic Hormones; D007457:Iodine Radioisotopes; D008543:Melanins; D009281:Naphthalenes; D010446:Peptide Fragments; D010907:Pituitary Hormones; D011979:Receptors, Pituitary Hormone; C457679:T-226296; C092274:melanin-concentrating hormone receptor; D016718:Arachidonic Acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C019463:melanin-concentrating hormone; D000242:Cyclic AMP; D002118:Calcium