title: Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists.
abstract: In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. ryo.naito@jp.astellas.com
authors.forename: Ryo
authors.initials: R
authors.lastname: Naito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yonetoku
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Toyoshima
authors.forename: Ken
authors.initials: K
authors.lastname: Ikeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D005260:Female; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012463:Saliva / Q000378:metabolism; D000069464:Solifenacin Succinate; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy
chemical_list: D018727:Muscarinic Antagonists; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D044005:Tetrahydroisoquinolines; D000069464:Solifenacin Succinate