Arizona Health Sciences

Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif.

TitlePotency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif.
Publication TypeJournal Article
Year of Publication2015
AuthorsFrankowski KJ, Slauson SR, Lovell KM, Phillips AM, Streicher JM, Zhou L, Whipple DA, Schoenen FJ, Prisinzano TE, Bohn LM, Aubé J
JournalBioorg Med Chem
Volume23
Issue14
Pagination3948-56
Date Published2015 Jul 15
ISSN1464-3391
KeywordsAnimals, Arrestins, Benzamides, beta-Arrestins, Chemistry Techniques, Synthetic, CHO Cells, Cricetulus, Drug Evaluation, Preclinical, Guanosine 5'-O-(3-Thiotriphosphate), Humans, Naltrexone, Narcotic Antagonists, Receptors, Opioid, kappa, Structure-Activity Relationship, Sulfonamides, Tetrahydroisoquinolines
Abstract

Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.

DOI10.1016/j.bmc.2014.12.033
Alternate JournalBioorg. Med. Chem.
PubMed ID25593096
PubMed Central IDPMC4468036
Grant ListR01 DA031927 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD