用于表征阿片受体异聚体的调谐亲和力二价配体
Tuned-Affinity Bivalent Ligands for the Characterization of Opioid Receptor Heteromers.
作者信息
Harvey Jessica H, Long Darcie H, England Pamela M, Whistler Jennifer L
机构信息
Ernest Gallo Clinic and Research Center, 5858 Horton St. Ste. 200, Emeryville, CA 94608 ; University of California, San Francisco, Genentech Hall, 600 16 St., San Francisco, CA 94158.
出版信息
ACS Med Chem Lett. 2012 Aug 9;3(8):640-644. doi: 10.1021/ml300083p.
Abstract
Opioid receptors, including the mu and delta opioid receptors (MOR and DOR) are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers compared to DOR homomers. Here we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.
摘要
阿片受体，包括μ和δ阿片受体（MOR和DOR）是治疗疼痛的重要靶点。尽管越来越多的证据表明这些受体形成异聚体，但MOR/DOR异聚体的功能作用仍未明确。我们设计并合成了二价配体作为工具来阐明MOR/DOR异聚体的功能作用。我们的配体（L2和L4）由一个对DOR亲和力低的化合物与一个对MOR亲和力高的化合物连接而成，目的是产生与DOR同聚体相比对MOR/DOR异聚体具有“调节亲和力”的配体。在此我们表明，与DOR同聚体相比，L2和L4在MOR/DOR异聚体上均表现出增强的亲和力，从而为剖析MOR/DOR异聚体在疼痛中的作用提供了独特的药理学工具。
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