Conformation-activity study of 4-phenylpiperidine analgesics.
A conformational study of various 4-phenylpiperidine analgesics (the prodines, ketobemidone, meperidine, and 1,3,4-trimethyl-4-phenylpiperidines) has been performed with Allinger's Molecular Mechanics II (MM2) program. Phenyl equatorial conformations were found to be preferred for the prodines, ketobemidone, and meperidine. For ketobemidone and meperidine, however, phenyl axial conformations were computed to be only 0.7 and 0.6 kcal/mol higher in energy. It was suggested that phenyl axial conformers can explain the potency-enhancing effect of a phenyl m-hydroxy group in these two compounds. In contrast, phenyl axial conformers were computed to be 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. In addition, relative concentrations of an analgesic conformation can be related to the potencies of the three prodines. A phenyl axial conformer was computed to be 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 found to be especially destabilized by a 3-methyl group in the beta configuration due to the steric crowding of the three piperidine substituents. Detailed comparisons were made between the computed structures and those observed by X-ray crystallography.
D000700:Analgesics / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D008614:Meperidine / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000700:Analgesics; D010880:Piperidines; D008614:Meperidine