title: Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.
abstract: To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
authors.affiliation: Banyu Tsukuba Research Institute, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.
authors.forename: Yufu
authors.initials: Y
authors.lastname: Sagara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sagara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mase
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Numazawa
authors.forename: Toru
authors.initials: T
authors.lastname: Fujikawa
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Noguchi
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
mesh_terms: D000109:Acetylcholine; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002217:Carbachol; D018678:Cholinergic Agents; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018678:Cholinergic Agents; D004151:Dipeptides; D018727:Muscarinic Antagonists; C448635:N-(2-(3-((1-(cyclohexylmethyl)-3-piperidinyl)methylamino)-3-oxopropyl)amino-2-oxoethyl)-3,3,3-triphenylpropionamide; D010880:Piperidines; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D002217:Carbachol; D000109:Acetylcholine