Synthesis and Pharmacological Evaluation of 2-(3-Piperidyl)-1,2,3,4-tetrahydroisoquinoline Derivatives as Specific Bradycardic Agents

• Published in: Chemical & Pharmaceutical Bulletin Vol. 51; no. 4; pp. 390 - 398
• Main Authors: Kakefuda, Akio, Watanabe, Toshihiro, Taguchi, Yasuko, Masuda, Noriyuki, Tanaka, Akihiro, Yanagisawa, Isao
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 2003; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: 1,2,3,4-tetrahydroisoquinoline; Animals; Antiarythmic agents; Biological and medical sciences; Bradycardia - chemically induced; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacology; Cardiovascular system; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; dimethoxy; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Guinea Pigs; Heart Rate - drug effects; Heart Rate - physiology; In Vitro Techniques; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Male; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Rats; Rats, Wistar; Science & Technology; specific bradycardic agent; Structure-Activity Relationship; Tetrahydroisoquinolines; Zatebradine; 1,2,3,4-tetrahydroisoquinoline; dimethoxy; DOGS; UL-FS-49; UL-FS 49; DYSFUNCTION; specific bradycardic agent; zatebradine; OCCLUSION; EXERCISE; Isoquinoline derivatives; Intravenous administration; Rat; Nitrogen heterocycle; Rodentia; Antiarrhythmic agent; In vitro; In vivo; Zatebradine; Vertebrata; Mammalia; Structure activity relation; Animal; Six membered ring; Piperidine derivatives; Bicyclic compound; Aromatic compound; Chemical synthesis
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.51.390

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.