| Literature DB >> 27797517 |
Cyf N Ramos-Colon1, Yeon Sun Lee1, Michael Remesic1, Sara M Hall1, Justin LaVigne1, Peg Davis1, Alexander J Sandweiss1, Mary I McIntosh1, Jessica Hanson1, Tally M Largent-Milnes1, Todd W Vanderah1, John Streicher1, Frank Porreca1, Victor J Hruby1.
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 Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 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-Arg7]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.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27797517 PMCID： PMC5693303 DOI： 10.1021/acs.jmedchem.6b01411
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446