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

Authors: Frankowski KJ, Slauson SR, Lovell KM, Phillips AM, Streicher JM, Zhou L, Whipple DA, Schoenen FJ, Prisinzano TE, Bohn LM, Aubé J.
Publisher/Year: Bioorg Med Chem S0968-0896(14)00881-5.
Pub Med ID/Journal ID: PMID:25593096


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.