title: Synthesis and pharmacological evaluation of 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives as specific bradycardic agents.
abstract: Novel 1,2,3,4-tetrahydroisoquinoline derivatives bearing directly a cyclic amine at the 2-position were prepared and examined for their bradycardic activities in isolated right atria and in anesthetized rats. The structure-activity relationships (SAR) study revealed that the 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline skeleton is essential for the appearance of potent in vitro activity, and that the presence of at least one methoxy group at the 6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline ring is important to exert potent in vitro activity. In vivo tests of selected compounds demonstrated that 2-(1-benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6c) exhibited potent bradycardic activity with negligible influence on mean blood pressure in rats, although its potency is a half of that of Zatebradine.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. kakefuda@yamanouchi.co.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Kakefuda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Taguchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tanaka
authors.forename: Isao
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000139:chemically induced*; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
chemical_list: D002316:Cardiotonic Agents; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline