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.
Kubota
Hideki
H
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. kubota.hideki@yamanouchi.co.jp
Watanabe
Toshihiro
T
Kakefuda
Akio
A
Masuda
Noriyuki
N
Wada
Kouichi
K
Ishii
Noe
N
Sakamoto
Shuichi
S
Tsukamoto
Shinichi
S
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