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dc.contributor.authorJoshi, Anand Anant
dc.contributor.authorMurray, Thomas F.
dc.contributor.authorAldrich, Jane V.
dc.identifier.citationJoshi, A. A., Murray, T. F., & Aldrich, J. V. (2015). Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin. Journal of Medicinal Chemistry, 58(22), 8783–8795.
dc.description.abstractThe dynorphin (Dyn) A analog zyklophin ([N-benzyl-Tyr1-cyclo(D-Asp5,Dap8)]dynorphin A(1-11)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 analogs to explore the structure-activity relationships of this peptide. The synthesis of selected analogs 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 the N-cyclopropylmethyl substitutions resulted in the analogs with the highest KOR affinities. Pharmacological results for the alanine-substituted analogs indicated that Phe4 and Arg6, but interestingly not the Tyr1, phenol are important for zyklophin’s KOR affinity, and Arg7 was important for KOR antagonist activity. In the GTPγS assay while all of the cyclic analogs exhibited negligible KOR efficacy, the N-phenethyl-Tyr1, N-CPM-Tyr1 and the N-benzyl-Phe1 analogs were 8- to 24-fold more potent KOR antagonists than zyklophin.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsPer SHERPA/RoMEO 4/18/2017: Author's Pre-print: grey tick subject to Restrictions below, author can archive pre-print (ie pre-refereeing) Restrictions:

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dc.titleStructure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophinen_US
kusw.kuauthorJoshi, Anand A.
kusw.kuauthorAldrich, Jane V.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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