Conformation activity study of 4-phenylpiperidine analgesics

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Abstract
A conformational study of various 4-phenylpiperidine analgesics (the prodines, ketobemidone, meperidine and 1,3,4-trimethyl-4-phenylpiperidines) was performed with Allinger''s Molecular Mechanics II (MM2) program. Phenyl equatorial conformations were preferred for the prodines, ketobemidone and meperidine. For ketobemidone and meperidine, phenyl axial conformations were 0.7 and 0.6 kcal/mol higher in energy. Phenyl axial conformers may explain the potency-enhancing effect of a phenyl m-hydroxy group in these 2 compounds. Phenyl axial conformers were relatively unfavorable for the prodines, being 1.9, 2.8 and 3.4 kcal/mol higher in energy for 3-demethyl-, .alpha.- and .beta.-prodine, respectively. Relative concentrations of an analgesic conformation can be related to the potencies of the 3 prodines. A phenyl axial conformer was preferred by 0.7 kcal/mol for the 3-demethyl compound of 1,3,4-trimethyl-4-phenylpiperidine, with phenyl equatorial conformers preferred by 1.3 and 3.3 kcal/mol for the .alpha. and .beta. compounds. Phenyl axial conformers were unexpectedly especially destabilized by a 3-methyl group in the .beta. configuration due to the steric crowding of the 3 piperidine substituents. Detailed comparisons were made between the computed structures and those observed by X-ray crystallography.