Balboni Gianfranco, Salvadori Severo, Trapella Claudio, Knapp Brian I, Bidlack Jean M, Lazarus Lawrence H, Peng Xuemei, Neumeyer John L
Department of Toxicology, University of Cagliari, I-09124, Cagliari, Italy.
ACS Chem Neurosci. 2010 Feb 17;1(2):155-164. doi: 10.1021/cn900025j.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.
基于双功能或多功能阿片类药物最近重新受到的重视，我们报告了一些源自我们的先导μ激动剂/δ拮抗剂H-Dmt-Tic-Gly-NH-Bzl的类似物的合成及药理学评价。我们之前的研究聚焦于C末端苄基官能团在诱导这种双功能活性中的重要性。发现在苯环的对位引入一些取代基（-Cl、-CH(3)、部分-NO(2)、无活性的-NH(2)）会产生更强的μ激动剂/拮抗剂效应，同时δ拮抗剂活性相对未改变（pA(2)=8.28 - 9.02）。增加苄基的空间位阻（使用二苯甲基和四氢异喹啉官能团）基本维持了先导化合物的μ激动剂和δ拮抗剂活性。最后且相当出乎意料的是，D-Tic2现在被认为是错误的阿片类信息；将其代替L-Tic插入参考化合物中，得到了一种比我们的参考配体（H-Dmt-Tic-Gly-NH-Ph）更好的μ激动剂/δ激动剂，并且具有相同的药理学特征。
