Synthesis and pharmacological evaluation of 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives as specific bradycardic agents |
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Authors: | Kakefuda Akio Watanabe Toshihiro Taguchi Yasuko Masuda Noriyuki Tanaka Akihiro Yanagisawa Isao |
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Institution: | Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. kakefuda@yamanouchi.co.jp |
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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. |
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