Conformational Properties of 3‐Phenylpiperidine and 3‐Phenylpyrrolidine Opioid Analgesics

Conformational energy calculations have been performed on 3‐phenylpiperidine and 3‐phenylpyrrolidine opioids using the MM2 method. Phenyl equatorial conformers were found to be preferred for 1,2,3‐trimethyl‐3‐phenylpiperidines while phenyl axial conformers were preferred for the 2‐demethyl derivative and 1‐methyl‐3‐isobutyl‐3‐phenylpyrrolidine. These conformational differences may account for differences in their structure‐activity relationships. The geometries of these compounds were superimposed onto a rigid phenyl‐axial opioid with the result that the more active antipodes of alpha‐2,3‐dimethyl‐3‐phenylpiperidine and 3‐isobutyl‐3‐phenylpyrrolidine antagonists were found to be a better fit. However, for the beta derivative, which has not yet been resolved, the opposite antipode was found to be a better fit though the orientation of NH bond was quite different. There is a good agreement between the computed molecular geometries and those observed by x‐ray crystallography.