title: 1,6-Dihydro-2H-indeno[5,4-b]furan derivatives: design, synthesis, and pharmacological characterization of a novel class of highly potent MT₂-selective agonists.
abstract: A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified as a potent mimic of the 5-methoxy indole core of melatonin, and introduction of a cyclohexylmethyl group at the 7-position of this scaffold afforded an MT(2)-selective ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound 15 was identified as a potent full agonist for the MT(2) subtype and exhibited reentrainment effects to a new light/dark cycle in ICR mice at 3-30 mg/kg. This result demonstrated the involvement of the MT(2) receptors in chronobiotic activity.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 17-85 Jusohonmachi, 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. Koike_Tatsuki@takeda.co.jp
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koike
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Hoashi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Takai
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Yukuhiro
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hirai
authors.forename: Osamu
authors.initials: O
authors.lastname: Uchikawa
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002940:Circadian Rhythm; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D003624:Darkness; D006801:Humans; D008024:Ligands; D008027:Light; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D044122:Receptor, Melatonin, MT1 / Q000819:agonists; D044123:Receptor, Melatonin, MT2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D001572:Benzofurans; D008024:Ligands; C559869:N-(2-(7-(cyclohexylmethyl)-1,6-dihydro-2H-indeno(5,4-b)furan-8-yl)ethyl)acetamide; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D000242:Cyclic AMP