Fries D S, Dodge R P, Hope H, Portoghese P S
J Med Chem. 1982 Jan;25(1):9-12. doi: 10.1021/jm00343a002.
Enantiomers of beta-1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine (4) were employed as probes to demonstrate that opioid receptors are capable of distinguishing between the enantiotopic edges (the Ogston effect) of the piperidine ring. These enantiomers, (-)- and (+)-4.HCl, were prepared by esterification of the corresponding alcohols, (+)- and (-)-4a. Single crystal X-ray studies of (-)-4a.HCl reveal that it possesses the 2R,4S absolute configuration. Analgetic testing in mice (hot-plate) and receptor binding studies indicate that (-)-(2S,4R)-4.HCl is approximately ten times more potent than its enantiomer. The results are consistent with the operation of the Ogston effect in the interaction of achiral 4-phenylpiperidines with opioid receptors. Additionally, it is suggested that the piperidine ring of these and other closely related 4-phenylpiperidines bind within a receptor subsite cleft whose dimensions exclude diequatorial 2,6- and 3,5-dimethyl-substituted ligands.
β-1,2-二甲基-4-苯基-4-(丙酰氧基)哌啶(4)的对映体被用作探针，以证明阿片受体能够区分哌啶环的对映异位边缘(奥格斯顿效应)。这些对映体，(-)-和(+)-4.HCl，是通过相应醇(+)-和(-)-4a的酯化反应制备的。(-)-4a.HCl的单晶X射线研究表明它具有2R,4S绝对构型。在小鼠身上进行的镇痛测试(热板法)和受体结合研究表明，(-)-(2S,4R)-4.HCl的效力约为其对映体的十倍。这些结果与非手性4-苯基哌啶与阿片受体相互作用中的奥格斯顿效应一致。此外，有人提出，这些及其他密切相关的4-苯基哌啶的哌啶环在一个受体亚位点裂隙内结合，该裂隙的尺寸排除了二平伏键的2,6-和3,5-二甲基取代配体。
