NONSYMMETRICAL BIPIPERIDYLS AS INHIBITORS OF VESICULAR ACETYLCHOLINE STORAGE

Introduction of a nitrogen atom into the cyclohexane ring of 2-(4-phen ylpiperidinyl)cyclohexanol (vesamicol, AH5183) yielded two positional isomers, 5-azavesamicol (5, prezamicol) and 4-aza-vesamicol (6, trozam icol). As inhibitors of vesicular acetylcholine transport, 5 and 6 wer e found to be 147 and 85 times less potent than vesamicol. N-Benzoylat ion of 5 (to yield 9a) increased the potency 3-fold. In contrast, 10a, a compound derived from N-benzoylation of 6, was 50 times more potent than the latter and almost equipotent with vesamicol, thereby suggest ing a preference for the 4-azavesamicol series. Although (-)-vesamicol is more potent than its dextrorotary isomer, (+)-10a was found to be 3 times more potent than (-)-10a, suggesting a reversal of the sign of rotation in the azavesamicol series. Reduction of 9a and 10a (to yiel d the corresponding N-benzyl derivatives 11a and 12a) increased potenc y 20- and 2-fold, respectively, indicating a preference for a basic ni trogen. The reaction of 5 or 6 with substituted benzyl halides yielded several potent inhibitors of vesicular acetylcholine transport, inclu ding N-(p-fluorobenzyl)trozamicol, 12d, which is twice as potent as ve samicol. Thus the introduction of a nitrogen atom into the cyclohexane ring of vesamicol provides opportunities for developing a new class o f anticholinergic agents.