Heyl D L, Mosberg H I
College of Pharmacy, University of Michigan, Ann Arbor 48109.
J Med Chem. 1992 May 1;35(9):1535-41. doi: 10.1021/jm00087a006.
In an effort to explore structural features affecting receptor recognition in a series of conformationally restricted tetrapeptides related to the cyclic, delta opioid receptor-selective analogue, [formula: see text] electronic, lipophilic, and steric effects at the Phe3 residue were assessed by substitution at different positions of the side-chain aromatic ring by halogens, alkyl, hydroxyl, and nitro groups. Effects on opioid receptor binding affinity and selectivity were determined. The results, which are generally consistent with reports of analogous modifications in linear and cyclic pentapeptide enkephalins, indicate that steric, lipophilic, and electronic properties are all important determinants of delta opioid receptor recognition. Specifically, modifications which increase lipophilicity or exert electron-withdrawing effects on the aromatic ring enhance binding affinity, while hydrophilic, bulky, or electron-releasing modifications are detrimental. These observations are in excellent agreement with quantitative structure-activity relationship (QSAR) results reported for Phe4 modifications in linear opioid pentapeptide enkephalin analogues, suggesting that the Phe3 tetrapeptide side chain and the Phe4 pentapeptide side chain interact with the same delta receptor binding subsite.
为了探究在一系列与环型δ阿片受体选择性类似物相关的构象受限四肽中影响受体识别的结构特征，[分子式：见原文]通过在侧链芳香环的不同位置用卤素、烷基、羟基和硝基取代，评估了苯丙氨酸3（Phe3）残基处的电子、亲脂性和空间效应。确定了对阿片受体结合亲和力和选择性的影响。这些结果总体上与线性和环型五肽脑啡肽类似修饰的报道一致，表明空间、亲脂性和电子性质都是δ阿片受体识别的重要决定因素。具体而言，增加亲脂性或对芳香环施加吸电子效应的修饰会增强结合亲和力，而亲水性、庞大或供电子修饰则不利。这些观察结果与线性阿片五肽脑啡肽类似物中苯丙氨酸4（Phe4）修饰的定量构效关系（QSAR）结果非常一致，表明Phe3四肽侧链和Phe4五肽侧链与同一δ受体结合亚位点相互作用。
