Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin
作者： Anand A. Joshi , Thomas F. Murray , Jane V. Aldrich
DOI: 10.1021/JM501827K
关键词: Structure–activity relationship 、 Chemistry 、 Antagonist 、 Dynorphin 、 Stereochemistry 、 Pharmacology 、 Opioid 、 κ-opioid receptor 、 Dynorphin A 、 Peptide 、 Receptor
摘要: The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d-Asp(5),Dap(8))]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, active vivo, and antagonizes KOR the CNS after systemic administration. Hence, we synthesized analogues to explore structure-activity relationships of this peptide. synthesis selected required modification introduce N-terminal amino acid due poor solubility and/or avoid epimerization residue. Among modifications, N-phenethyl N-cyclopropylmethyl substitutions resulted with highest affinities. Pharmacological results for alanine-substituted indicated that Phe(4) Arg(6), but interestingly not Tyr(1) phenol, are important zyklophin's affinity Arg(7) was activity. In GTPγS assay, while all cyclic exhibited negligible efficacy, N-cyclopropylmethyl-Tyr(1) N-benzyl-Phe(1) were 28- 11-fold more potent antagonists, respectively, than zyklophin.
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