基于阿片样物质和胆囊收缩素受体上重叠药效基团的双功能环二硫肽的构效关系。
Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors.
作者信息
Agnes Richard S, Ying Jinfa, Kövér Katalin E, Lee Yeon Sun, Davis Peg, Ma Shou-wu, Badghisi Hamid, Porreca Frank, Lai Josephine, Hruby Victor J
机构信息
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
出版信息
Peptides. 2008 Aug;29(8):1413-23. doi: 10.1016/j.peptides.2008.03.022. Epub 2008 Apr 10.
Abstract
Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH(2)) showed potent binding and agonist activities at delta and mu opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.
摘要
长期暴露于阿片类药物会增加中枢神经系统（CNS）中胆囊收缩素（CCK）及其受体的表达，在中枢神经系统中CCK可能会减弱阿片类药物的镇痛作用。阿片类药物与CCK之间的复杂相互作用可能在阿片类药物耐受性的发展中起作用。我们设计并合成了环状二硫肽，并确定了它们在阿片受体上的激动剂特性以及在CCK受体上的拮抗剂特性。化合物1（Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH(2)）在δ和μ阿片受体上表现出强效的结合和激动活性，但与CCK受体的结合较弱。先导化合物的核磁共振结构显示出与阿片类药物和CCK配体相似的构象特征。
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