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

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.

Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting

“…We have previously reported on a novel series of KOR antagonists based on a sulfonamide scaffold (Frankowski et al, 2014). Compound 1 (Figure 7 A) has higher affinity for KOR over DOR and MOR when evaluated in CHO cells overexpressing the human MOR, DOR or KOR (Figure 7B).…”

Seeking (and Finding) Biased Ligands of the Kappa Opioid Receptor

“…Such studies were carried out using endogenous agonistic dynorphin peptides, the literature antagonists norBNI and 5′-GNTI, and an example of the sulfonamide class discovered in the course of our MLI work. 18,42 Besides showing that the activity of these agents could be reproduced in this closer-to-realistic cellular environment (as opposed to transfected CHO cells), the use of parallel knockout models enabled the insight that some ligands generally considered to be selective in fact operate though both the KOR and MOR pathways.…”

Advances in Sulfonamide Kappa Opioid Receptor Antagonists: Structural Refinement and Evaluation of CNS Clearance

“…The [ 35 S]GTPγS binding assay was performed using membranes prepared from the CHO-hKOR cells according to our published protocols for this assay 21,22 as previously described to assess antagonist potency. 13 Data Analysis and Statistics. The GraphPad Prism 6.01 software (GraphPad) was used to generate sigmoidal concentration−response curves using a three-parameter, nonlinear regression analysis.…”

“…HPLC/MS analysis was carried out with gradient elution (5% CH 3 CN to 100% CH 3 CN) on an Agilent 1200 RRLC with a photodiode array UV detector (214 nm) and an Agilent 6224 TOF mass spectrometer (also used to produce high-resolution mass spectra). 1 H and 13 C NMR spectra were acquired on a 600 MHz Bruker AVIII spectrometer equipped with a cryogenically cooled carbon observe probe, a 500 MHz Bruker AVIII spectrometer equipped with a cryogenically cooled carbon observe probe, a 400 MHz Bruker AVIIIHD spectrometer, or a 400 MHz Varian 400MR spectrometer. HRMS data were collected with an LCT Premier time-of-flight mass spectrometer and an electrospray ion source.…”