新型单和双价吗啡烷配体对 κ、μ 和 δ 阿片受体的合成和结合亲和力。
Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for κ, μ, and δ opioid receptors.
机构信息
Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478-9106, USA.
出版信息
Bioorg Med Chem. 2011 May 1;19(9):2808-16. doi: 10.1016/j.bmc.2011.03.052. Epub 2011 Mar 26.
Abstract
A novel series of homo- and heterodimeric ligands containing κ/μ agonist and μ agonist/antagonist pharmacophores joined by a 10-carbon ester linker chain were synthesized and evaluated for their in vitro binding affinity at κ, μ, and δ opioid receptors, and their functional activities were determined at κ and μ receptors in [(35)S]GTPγS functional assays. Most of these compounds had high binding affinity at μ and κ receptors (K(i) values less than 1nM). Compound 15b, which contains butorphan (1) at one end of linking chain and butorphanol (5) at the other end, was the most potent ligand in this series with binding affinity K(i) values of 0.089nM at the μ receptor and 0.073nM at the κ receptor. All of the morphinan-derived ligands were found to be partial κ and μ agonists; ATPM-derived ligands 12 and 11 were found to be full κ agonists and partial μ agonists.
摘要
合成了一系列新型的同型和异型二聚体配体，这些配体含有 κ/μ 激动剂和 μ 激动剂/拮抗剂药效团，通过 10 个碳酯键连接链连接在一起，并在体外对 κ、μ 和 δ 阿片受体进行了结合亲和力评估，同时在 [(35)S]GTPγS 功能测定中测定了它们在 κ 和 μ 受体上的功能活性。这些化合物中的大多数在 μ 和 κ 受体上具有高的结合亲和力（K(i) 值小于 1nM）。化合物 15b 在连接链的一端含有丁丙诺啡（1），在另一端含有丁丙诺啡（5），是该系列中最有效的配体，对 μ 受体的结合亲和力 K(i) 值为 0.089nM，对 κ 受体的结合亲和力 K(i) 值为 0.073nM。所有来源于吗啡烷的配体均被发现为部分 κ 和 μ 激动剂；来源于 APTM 的配体 12 和 11 被发现为完全 κ 激动剂和部分 μ 激动剂。
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本文引用的文献
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2
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