Froimowitz M
J Med Chem. 1982 Oct;25(10):1127-33. doi: 10.1021/jm00352a006.
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.
利用阿林格分子力学II（MM2）程序对各种4-苯基哌啶类镇痛药（丙氧芬、凯托米酮、哌替啶和1,3,4-三甲基-4-苯基哌啶）进行了构象研究。发现丙氧芬、凯托米酮和哌替啶的苯基处于平伏键构象更为有利。然而，对于凯托米酮和哌替啶，计算得出苯基处于直立键构象的能量仅分别高0.7和0.6千卡/摩尔。有人提出，苯基直立键构象可以解释这两种化合物中苯基间位羟基的增效作用。相比之下，计算得出苯基直立键构象对丙氧芬相对不利，对于3-去甲基丙氧芬、α-丙氧芬和β-丙氧芬，其能量分别高1.9、2.8和3.4千卡/摩尔。此外，镇痛构象的相对浓度与三种丙氧芬的效力有关。计算得出1,3,4-三甲基-4-苯基哌啶的3-去甲基化合物中苯基直立键构象比平伏键构象更稳定0.7千卡/摩尔，而α和β化合物中苯基平伏键构象分别比直立键构象稳定1.3和3.3千卡/摩尔。由于哌啶的三个取代基的空间拥挤，意外地发现β构型的3-甲基会使苯基直立键构象特别不稳定。对计算得到的结构与通过X射线晶体学观察到的结构进行了详细比较。
