Loew G H, Berkowitz D S, Burt S K
NIDA Res Monogr. 1978(22):278-316.
Three classes of flexible opiates have been studied: 4-phenyl piperdines, methadone and enkephalins. Our results show that low energy conformers of the 4-phenyl piperidines have equatorial phenyl rings and cannot completely overlap with rigid opiates at the receptor. A combination of calculated conformational and electronic properties could account for observed potency differences in meperidine, desmethyl, alpha+, alpha-, beta+ and beta- prodines. Our results also indicate that both meperidine and its reverse ester bind to the receptor in a similar mode with the phi ring in approximmately the same position as the phenyl substituent in 5-phenyl benzomorphans. Conformers of methadone which maximally resemble morphine have very high relative energies. The lowest energy conformer has a partial H-bond between the NH and O=C groups. In this conformation methadone resembles meperidine more than morphine. The electronic structure of all three types of opiates indicate a similar cationic charge distribution around the amine nitrogen and imply that their binding to an anionic receptor site could be similar. The determination of peptide opiate conformations present a challenge of a different order of magnitude than the most flexibe exogenous opiates. Because of the extremely large number of possible conformations, search strategies based on energy optimized conformations alone are not adequate to select plausible receptor site candidates. Other criteria such as consistency with known structure activity data and similarities to rigid opiates must be used. With this rationale, we have predicted and characterized a low energy conformer of Met-enkephalin and D-ala2 Met-enkephalin as a likely candidate at the receptor site. With a modest energy input (deltaE approximately 3 kcal/mole) significant overlap of this conformer with the potent opiate PET was obtained. The tyrosine and phenyalanine side chains and the terminal amine and carboxyl groups play a crucial role in this overlap. It is hoped that this calculation with help establish a template for peptide opiate receptor interactions.
4-苯基哌啶类、美沙酮和脑啡肽。我们的结果表明，4-苯基哌啶类的低能量构象异构体具有平伏苯基环，在受体处不能与刚性阿片类药物完全重叠。计算得到的构象和电子性质的组合可以解释哌替啶、去甲基、α+、α-、β+和β-丙替啶中观察到的效价差异。我们的结果还表明，哌替啶及其反式酯以相似的模式与受体结合，其φ环的位置与5-苯基苯并吗啡烷中的苯基取代基大致相同。与吗啡最大程度相似的美沙酮构象异构体具有非常高的相对能量。能量最低的构象异构体在NH和O=C基团之间存在部分氢键。在这种构象中，美沙酮与哌替啶的相似性超过与吗啡的相似性。所有这三种类型阿片类药物的电子结构表明，胺氮周围存在相似的阳离子电荷分布，这意味着它们与阴离子受体位点的结合可能相似。确定肽类阿片的构象带来了与最柔性的外源性阿片类药物不同数量级的挑战。由于可能的构象数量极多，仅基于能量优化构象的搜索策略不足以选择合理的受体位点候选物。必须使用其他标准，如与已知构效关系数据的一致性以及与刚性阿片类药物的相似性。基于这一基本原理，我们预测并表征了甲硫氨酸脑啡肽和D-丙氨酸2-甲硫氨酸脑啡肽的一种低能量构象异构体，它可能是受体位点的候选物。通过适度的能量输入（ΔE约为3千卡/摩尔），该构象异构体与强效阿片类药物PET有显著重叠。酪氨酸和苯丙氨酸侧链以及末端胺基和羧基在这种重叠中起关键作用。希望这种计算有助于建立肽类阿片受体相互作用的模板。
