Frankowski, Kevin J.Slauson, Stephen R.Movell, Kimberly M.Phillips, Angela M.Streicher, John M.Zhou, LeiWhipple, David A.Schoenen, Frank J.Prisinzano, Thomas E.Bohn, Laura M.Aubé, Jeffrey2017-05-102017-05-102015-07-15Frankowski, K. J., Slauson, S. R., Lovell, K. M., Phillips, A. M., Streicher, J. M., Zhou, L., … Aubé, J. (2015). Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif. Bioorganic & Medicinal Chemistry, 23(14), 3948–3956. http://doi.org/10.1016/j.bmc.2014.12.033https://hdl.handle.net/1808/24079Optimization 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.This article is made available under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND 3.0) License.https://creativecommons.org/licenses/by-nc-nd/3.0/Kappa Opioid ReceptorAntagonistMolecular constraintPotency enhancementTetrahydroisoquinolineArticle10.1016/j.bmc.2014.12.033https://orcid.org/0000-0003-1049-5767 https://orcid.org/0000-0002-2811-2894PMC4468036openAccess