Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl 1,2,3,4-Tetrahydroisoquinoline-2-carboxylate Derivatives as Novel Muscarinic Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 48; no. 21; pp. 6597 - 6606
• Main Authors: Naito, Ryo, Yonetoku, Yasuhiro, Okamoto, Yoshinori, Toyoshima, Akira, Ikeda, Ken, Takeuchi, Makoto
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.10.2005; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Female; Life Sciences & Biomedicine; Models, Molecular; Muscarinic Antagonists - chemical synthesis; Muscarinic Antagonists - chemistry; Muscarinic Antagonists - pharmacology; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Pharmacology & Pharmacy; Quinuclidines - chemical synthesis; Quinuclidines - chemistry; Quinuclidines - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptor, Muscarinic M3 - antagonists & inhibitors; Receptor, Muscarinic M3 - metabolism; Saliva - secretion; Science & Technology; Solifenacin Succinate; Stereoisomerism; Structure-Activity Relationship; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology; Urinary Bladder - drug effects; Urinary Bladder - physiology; Urinary Incontinence - drug therapy; ACID-DERIVATIVES; IN-VITRO; POTENT; ABSOLUTE-CONFIGURATION; URINARY-BLADDER; ESTERS; SOLIFENACIN SUCCINATE YM905; DISORDERS; AGENTS; SELECTIVITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050099q

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.