Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).
Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).
复制标题
开发 δ 阿片受体药效团模型。
DOI：
10.1021/jm00051a016
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发表时间：
1994
影响因子：
7.3
通讯作者：
Porreca,F
中科院分区：
文献类型：
--
作者：
Mosberg,HI;Omnaas,JR;Lomize,A;Heyl,DL;Nordan,I;Mousigian,C;Davis,P;Porreca,F
研究了ó阿片受体选择性四肽tyrc [D-Cys-Phe-D-Pen] OH （JOM-13）的体外药理学性质和构象特征，其中Phe3残基被/3-甲基苯基丙氨酸（/3-MePhe）的四个立体异构体中的每一个取代。在这两种类似物中，取代Phe3的a碳具有l -立体化学，对受体具有高亲和力，(2S, 3S)-MePhe3类似物的亲和力比（2S, 3i?）高约8倍。-MePhe3非对映异构体。令人惊讶的是，残基3中具有d立体化学的类似物（2ñ， 3i?）-MePhe3类似物，也对受体表现出高亲和力，并且对该受体具有极强的选择性。在小鼠输精管（MVD）和豚鼠回肠（GPI）平滑肌生物测定中，所有类似物都是激动剂，MVD和GPI的效力分别与其ó和µ阿片受体亲和力一致。使用/3- mephe作为Phe3的替代品是基于希望通过施加/3-甲基取代基形式的立体旋转约束来降低Phe3侧链的构象灵活性，从而从受体结合亲和力和构象偏好之间的相关性推断出受体结合构象中的残基3侧链取向。然而，分子力学计算表明，在(2S, 3S)-MePhe3和（2S, 3i?）-MePhe3类似物过于温和，无法明确确定受体结合残基3侧链的构象。然而，高亲和力(2i？, 32 ?)-MePhe3类似物显示出对单侧链构象（1~）的强烈偏好
The in vitro pharmacological properties and conformational features of analogs of the ó opioid receptor selective tetrapeptide Tyr-c [D-Cys-Phe-D-Pen] OH (JOM-13) in which the Phe3 residue was replaced by each of the four stereoisomers of/3-methylphenylalanine (/3-MePhe) were investigated. Both analogs in which the a carbon of the Phe3 replacement has L-stereochemistry display high affinity for receptors with the (2S, 3S)-MePhe3 analog exhibiting approximately 8-fold higher affinity than the (2S, 3i?)-MePhe3 diastereomer. Surprisingly, one analog with D-stereochemistry in residue 3, the (2ñ, 3i?)-MePhe3 analog, also displays high affinity for the receptor and is extraordinarily selective for this receptor. All analogs were agonists in the mouse vas deferens (MVD) and guinea pig ileum (GPI) smooth muscle bioassays, displaying MVD and GPI potencies consistent with their ó and µ opioid receptor affinities, respectively. The use of/3-MePhe as a replacement for Phe3 was based uponthe desire to reduce the conformational flexibility of the Phe3 side chain by imposing a steric rotational constraint in the form of the/3-methyl substituent and to thus deduce the residue 3 side chainorientation in the receptor-bound conformation from the correlation between receptor binding affinities and conformational preferences. Molecular mechanics computations revealed, however, that the conformational constraints imposed by the/3-methyl group in the (2S, 3S)-MePhe3 and (2S, 3i?)-MePhe3 analogs were too modest to allow unequivocal determination of receptor-bound residue 3 side chain conformation. However, analysis of the high-affinity (2i?, 32?)-MePhe3 analog revealed a strong preference for a single side chain conformer (1~