Preferred conformers for the pharmacologically typical and atypical antipodes of phenylmorphan opiates.

Abstract

The conformational preferences of phenylmorphan have been determined by the MM2 (Molecular Mechanics II) program using full energy minimization. Chair-chair conformations of the cyclohexane and piperidine rings were preferred by 2.6 kcal/mol or more. With the preferred chair-chair conformation, three stable orientations of the phenyl ring were found with relative energies of 0.0, 1.0, and 1.2 kcal/mol. The barrier to rotation of the phenyl ring was computed to be 4 kcal/mol. The preferred phenyl orientation for the (+)-antipode was similar to that of morphine using a previously postulated molecular model for opiate substrates. This is consistent with the typical morphine-like pharmacological properties of this antipode. The preferred phenyl orientation of the atypical (-)-antipode appears to be most similar to the phenyl orientation that is invariably preferred by more active prodine antipodes. The preferred conformer was similar to the one observed by X-ray crystallography.