Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States.
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.
J Med Chem. 2021 Mar 25;64(6):3153-3164. doi: 10.1021/acs.jmedchem.0c01984. Epub 2021 Mar 10.
Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and mood disorders. The linear acetylated dynorphin A analog arodyn (Ac[Phe,Arg,d-Ala]dynorphin A-(1-11)NH), synthesized in our laboratory, demonstrated potent and selective KOR antagonism. Cyclization of arodyn could potentially stabilize the bioactive conformation and enhance its metabolic stability. The cyclization strategy employed involved ring closing metathesis between adjacent - or -substituted Tyr(allyl) residues in the "message" sequence that were predicted in a docking study to yield analogs that would bind to the KOR with binding poses similar to arodyn. Consistent with the modeling, the resulting analogs retained KOR affinity similar to arodyn; the peptides involving cyclization between -allyl groups also retained high KOR selectivity, with one analog exhibiting KOR antagonist potency ( = 15 nM) similar to arodyn. These promising cyclized analogs with constrained aromatic residues represent novel leads for further exploration of KOR pharmacology.
κ 阿片受体（KOR）拮抗剂最近显示出在治疗药物成瘾和情绪障碍方面的潜力。我们实验室合成的线性乙酰化强啡肽 A 类似物 arodyn（Ac[Phe，Arg，d-Ala]dynorphin A-（1-11）NH）表现出强大和选择性的 KOR 拮抗作用。arodyn 的环化可能会稳定生物活性构象并提高其代谢稳定性。所采用的环化策略涉及在“消息”序列中相邻的 - 或 - 取代 Tyr（烯丙基）残基之间的闭环复分解反应，该反应在对接研究中预测会产生与 KOR 结合的类似物，其结合构象类似于 arodyn。与建模一致，所得类似物保留了与 arodyn 相似的 KOR 亲和力；涉及 - 烯丙基基团之间环化的肽也保留了高 KOR 选择性，一种类似物表现出与 arodyn 相似的 KOR 拮抗剂效力（=15 nM）。这些具有约束性芳香残基的有前途的环化类似物代表了进一步探索 KOR 药理学的新先导物。
