Probing the Stereochemical Requirements for Receptor Recognition of δ Opioid Agonists through Topographic Modifications in Position 1

化学 构象异构 立体化学 侧链 选择性 受体 分子模型 阿片受体 类阿片 分子 生物化学 催化作用 有机化学 聚合物
作者
Xinhua Qian,Mark D. Shenderovich,Katalin E. Kövér,Peg Davis,Rita Horvath,Teresa Zalewska,Henry I. Yamamura,Frank Porreca,Victor J. Hruby
出处
期刊:Journal of the American Chemical Society [American Chemical Society]
卷期号:118 (31): 7280-7290 被引量:66
标识
DOI:10.1021/ja954241w
摘要

A series of side-chain constrained tyrosine derivatives, 2‘,6‘-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-d-Pen2-Gly-Phe-d-Pen5-OH) and deltorphin I (DELT I, Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (−), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (−) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)-TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)-TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.
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