Literature DB >> 25593096

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

Kevin J Frankowski1, Stephen R Slauson1, Kimberly M Lovell2, Angela M Phillips2, John M Streicher2, Lei Zhou2, David A Whipple1, Frank J Schoenen1, Thomas E Prisinzano1, Laura M Bohn3, Jeffrey Aubé4.   

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.
Copyright © 2014 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Antagonist; Kappa opioid receptor; Molecular constraint; Potency enhancement; Tetrahydroisoquinoline

Mesh：

Substances：

Year:  2014        PMID： 25593096      PMCID： PMC4468036          DOI： 10.1016/j.bmc.2014.12.033

Source DB:  PubMed          Journal:  Bioorg Med Chem        ISSN： 0968-0896            Impact factor:   3.641


  17 in total

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