[Synthesis and biological activity of substituted benzyl/naphthylmethylisoquinolines and related quaternary ammonium derivatives].
In an attempt to search for novel antihypertensive or antiarrhythmic agents, especially compounds mainly acting on calcium or potassium channels, with the isoquinoline alkaloids which possessed cardiovascular effects as lead compounds, and on the basis of previous works of our laboratory as well as integration of the structural feature of certain potassium channel blockers, 28 compounds (I1-6 and II1-22) were designed and synthesized among which 24 were not reported previously. 3,4-Dihydroisoquinolines were first synthesized by the Bischler-Napieralski cyclization with 3,4-disubstituted phenethylamine and aromatic acetic acid as starting materials. N-alkyl substituted tetrahydroisoquinolines were prepared by the alkylation of tetrahydroisoquinolines with corresponding substituted benzyl halides, or by the reduction of dihydroisoquinoline quaternary ammonium derivatives. Preliminary pharmacological studies in vivo showed that most of these compounds exhibited various degrees of hypotensive and bradycardial effects except I4 which exhibited hypertensive activity. The hypotensive effect of II1 was the most potent among these compounds in anaesthetized normotensive Sprague-Dawley rats. Analysis of the QSAR between hypotensive/bradycardial activities of certain compounds and their structural parameters of molecular mechanics (MM2) showed that the hypotension/bradycardia increased with the increase/decrease of the charge of the nitrogen atom in the isoquinoline nucleus. Thus, the charge of the nitrogen atom might be one of the important factors which could enhance the selectivity of the compounds acting on blood vessels or cardiac tissues.
Xu
G Y
GY
Division of Medicinal Chemistry, China Pharmaceutical University, Nanjing.
Peng
S X
SX
Hua
W Y
WY
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D007546:Isoquinolines; D000644:Quaternary Ammonium Compounds