title: Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the κ Opioid Receptor.
abstract: Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Cyf N
authors: CN
authors: Ramos-Colon
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Yeon Sun
authors: YS
authors: Lee
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Michael
authors: M
authors: Remesic
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Sara M
authors: SM
authors: Hall
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Justin
authors: J
authors: LaVigne
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Peg
authors: P
authors: Davis
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Alexander J
authors: AJ
authors: Sandweiss
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Mary I
authors: MI
authors: McIntosh
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Jessica
authors: J
authors: Hanson
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Tally M
authors: TM
authors: Largent-Milnes
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Todd W
authors: TW
authors: Vanderah
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: John
authors: J
authors: Streicher
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Frank
authors: F
authors: Porreca
authors: Department of Pharmacology and Toxicology, ‡Department of Chemistry and Biochemistry, and §Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors: Victor J
authors: VJ
authors: Hruby
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D004399:Dynorphins