SYNTHESIS AND BIOLOGICAL ACTIVITY OF SUBSTITUTED BENZYL／NAPHTHYLMETHYLISOQUINOLINES AND RELATED QUATERNARY AMMONIUM DERIVATIVES

In an attempt to search for novel antihypertensive or antiarrhythmic agents,espe-cially compounds mainly acting on calcium or potassium channels,with the isoquinoline alkaloidswhich possessed cardiovascular effects as lead compounds , and on the basis of previous works of ourlaboratory as well as integration of the structural feature of certain potassium channel blockers,28compounds(I_1～6 and II_1～22) were designed and synthesized among which 24 were not reportedpreviously.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 tetrahy-droisoquinolines were prepared by the alkylation of tetrahydroisoquinolines with corresponding substitut-ed benzyl halides,or by the reduction of dihydroisoquinoline quaternary ammonium derivatives.Preliminary pharmacological studies in vivo showed that most of these com pounds exhibitedvarious degrees of hypotensive and bradycardial effects except I₄ which exhibited hypertensiveactivity.The hypotensive effect of II₁ was the most potent among these compounds in anaesthetizednormotensive Sprague-Dawley rats.Analysis of theQSAR between hypotensive/bradycardial activities of certain compounds and theirstructural parameters of molecular mechanics(MM₂)showed that the hypotension/ bradycardiaincreased with the increase/decrease of the charge of the n itrogen atom in the isoquinoline nucleus.Thus,the charge of the nitrogen atom might be one of the important factors which could enhance theselectivity of the compounds acting on blood vessels or cardiac tissues.