Structure-Activity Relationships of [des-Arg(7)]Dynorphin A Analogues at the κ Opioid Receptor.

TitleStructure-Activity Relationships of [des-Arg(7)]Dynorphin A Analogues at the κ Opioid Receptor.
Publication TypeJournal Article
Year of Publication2016
AuthorsRamos-Colon CN, Lee YSun, Remesic M, Hall SM, LaVigne J, Davis P, Sandweiss AJ, McIntosh MI, Hanson J, Largent-Milnes TM, Vanderah TW, Streicher J, Porreca F, Hruby VJ
JournalJ Med Chem
Date Published2016 Nov 23
KeywordsAnimals, Cell Line, CHO Cells, Cricetulus, Dose-Response Relationship, Drug, Dynorphins, Guinea Pigs, Male, Mice, Mice, Inbred ICR, Narcotic Antagonists, Pain, Rats, Receptors, Opioid, kappa, Structure-Activity Relationship

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 Arg(7) residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg(7)]Dyn A analogues found that Arg(7) is 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-Arg(7)]Dyn A(1-9)-NH2 is 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.

Alternate JournalJ. Med. Chem.
PubMed ID27797517
Faculty Member Reference: 
Victor Hruby, Ph.D.
Tally Largent-Milnes, PhD
Frank Porreca, PhD
John M. Streicher, PhD
Todd Vanderah, PhD