Structure鈥揂ctivity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin

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• 作者：Anand A. Joshi ; Thomas F. Murray ; Jane V. Aldrich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：8783-8795
• 全文大小：522K
• ISSN：1520-4804

文摘

The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr¹-cyclo(d-Asp⁵,Dap⁸)]dynorphin A(1鈥?1)NH₂) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure鈥揳ctivity relationships of this peptide. The synthesis of selected analogues required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N-terminal modifications, the N-phenethyl and N-cyclopropylmethyl substitutions resulted in analogues with the highest KOR affinities. Pharmacological results for the alanine-substituted analogues indicated that Phe⁴ and Arg⁶, but interestingly not the Tyr¹ phenol, are important for zyklophin鈥檚 KOR affinity and that Arg⁷ was important for KOR antagonist activity. In the GTP纬S assay, while all of the cyclic analogues exhibited negligible KOR efficacy, the N-cyclopropylmethyl-Tyr¹ and N-benzyl-Phe¹ analogues were 28- and 11-fold more potent KOR antagonists, respectively, than zyklophin.