Synthesis of 8-aryltetrahydroisoquinolines as dopamine antagonists and evaluation for potential neuroleptic activity.
The synthesis of 8-(methoxyphenyl)-1,2,3,4-tetrahydroisoquinolines using aryloxazolines as key intermediates is described. Nucleophilic displacement on an o-methoxyphenyloxazoline by an aryl Grignard reagent, followed by electrophilic substitution at the other ortho position, provided a specific route to the properly substituted benzene intermediates necessary for conversion to the tetrahydroisoquinolines. These compounds and 8-phenyl- and 2-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinolines, which are ring-opened analogues of apomorphine, were found to be dopamine antagonists by in vitro dopamine receptor studies. In vivo evaluation, however, did not substantiate potential usefulness as antipsychotic agents when they were compared with standard neuroleptic agents.
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis*; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive; D002417:Cattle; D002490:Central Nervous System / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists; D006220:Haloperidol / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007546:Isoquinolines; D011954:Receptors, Dopamine; D006220:Haloperidol; D004298:Dopamine