Novel tetracyclic spiropiperidines. 4. Synthesis and pharmacological evaluation of spiro- and 6,7-dihydrospiro[benzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-2 (1H),4'-piperidine]s.
A previously described series of 1-arylspiro[indoline-3,4'-piperidine]s was reported by us to possess significant antidepressant properties. This biological activity was found to be at a maximum among those compounds bearing an ortho substituent (e.g., NH2 as in 1) in the pendant aryl ring. In order to explore further this "ortho effect", we synthesized cyclic analogues of type 3 and 4 in which the position of the o-NH2-substituted aryl group is conformationally restricted and defined. When tested for antidepressant activity by tetrabenazine ptosis prevention in mice, it was found that restriction of rotation of the pendant o-aminophenyl group in these rigid analogues resulted in a loss of antidepressant properties. However, analgesic activity was retained and even improved by this molecular constraint.
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001681:Biological Assay; D001763:Blepharoptosis / Q000188:drug therapy; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013055:Spectrophotometry, Infrared; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013747:Tetrabenazine / Q000633:toxicity
D000928:Antidepressive Agents; D007202:Indicators and Reagents; D010880:Piperidines; D013141:Spiro Compounds; D001569:Benzodiazepines; D013747:Tetrabenazine