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

Bioorg Med Chem. 2015 Jul 15;23(14):3948-56. doi: 10.1016/j.bmc.2014.12.033.

Kevin J Frankowski ¹, Stephen R Slauson ¹, Kimberly M Lovell ², Angela M Phillips ², John M Streicher ², Lei Zhou ², David A Whipple ¹, Frank J Schoenen ¹, Thomas E Prisinzano ¹, Laura M Bohn ³, Jeffrey Aubé ⁴

Affiliations

1 University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA.
2 Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA.
3 Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.
4 University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA. Electronic address: jaube@ku.edu.

PMID: 25593096 DOI: 10.1016/j.bmc.2014.12.033

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.

Keywords

Antagonist; Kappa opioid receptor; Molecular constraint; Potency enhancement; Tetrahydroisoquinoline.

Name
Email *

	Sorry, but the email address you supplied was invalid.