Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin.
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, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-activity 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 Phe(4) and Arg(6), but interestingly not the Tyr(1) phenol, are important for zyklophin's KOR affinity and that Arg(7) was important for KOR antagonist activity. In the GTPγS assay, while all of the cyclic analogues exhibited negligible KOR efficacy, the N-cyclopropylmethyl-Tyr(1) and N-benzyl-Phe(1) analogues were 28- and 11-fold more potent KOR antagonists, respectively, than zyklophin.
Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
Anand A
AA
Joshi
Department of Pharmacology, School of Medicine, Creighton University , Omaha, Nebraska 68102, United States.
Thomas F
TF
Murray
Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
Jane V
JV
Aldrich
D000409:Alanine / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004399:Dynorphins / Q000737:chemistry / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D051379:Mice; D009292:Narcotic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009292:Narcotic Antagonists; D010446:Peptide Fragments; D010455:Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C502814:dynorphin A-(1-11)-NH2, Nalpha-benzylTyr(1)-cyclo(Asp(5)-Dap(8))-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004399:Dynorphins; D000409:Alanine