Synthesis and pharmacological evaluation of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel specific bradycardic agents.
A series of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for their bradycardic activities in isolated guinea pig right atria and in urethane-anesthetized rats. These efforts resulted in identification of the compound 8a, which exhibits potent bradycardic activity with minimal influence on mean blood pressure in urethane-anesthetized rats. Oral administration of compound 8a to conscious rats revealed increased potency and prolonged duration of action when compared to Zatebradine.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. kubota.hideki@yamanouchi.co.jp
Hideki
H
Kubota
Toshihiro
T
Watanabe
Akio
A
Kakefuda
Noriyuki
N
Masuda
Kouichi
K
Wada
Noe
N
Ishii
Shuichi
S
Sakamoto
Shinichi
S
Tsukamoto
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000188:drug therapy*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D044005:Tetrahydroisoquinolines; C043636:zatebradine