Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy

Abstract

Herein we present the outcome of a high throughput screening (HTS) campaign-based strategy for the rapid identification and optimization of selective and general chemotypes for both kappa (κ) opioid receptor (KOR) activation and inhibition. In this program, we have developed potent antagonists (IC50 < 120 nM) or agonists of high binding affinity (Ki < 3 nM). In contrast to many important KOR ligands, the compounds presented here are highly modular, readily synthesized and, in most cases, achiral. The four new chemotypes hold promise for further development into chemical tools for studying the KOR or as potential therapeutic lead candidates.

Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

“…However, the prototypical KOP receptor-selective non-peptide antagonists nor-BNI, 5′-guanidinylnaltrindole (GNTI) and JDTic exhibit exceptionally long activity, antagonizing KOP receptors for weeks after a single dose (Metcalf and Coop, 2005;). This profile could potentially complicate their use as pharmacological tools and as possible therapeutic agents, spurring the search for shorter acting KOP receptor-selective antagonists (Brugel et al, 2010;Runyon et al, 2010;Grimwood et al, 2011;Peters et al, 2011;Frankowski et al, 2012).…”

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

“…Unfortunately, this prolonged duration precludes certain key preclinical studies and could potentially impair clinical development. Recently, several new non-peptide KOR antagonists have been reported (Brugel et al, 2010;Runyon et al, 2010;Grimwood et al, 2011;Mitch et al, 2011;Peters et al, 2011;Frankowski et al, 2012), some of which demonstrated shorter durations of KOR antagonist activity (Runyon et al, 2010;Peters et al, 2011) or were detected for relatively short (<8 h) periods in the brain (Grimwood et al, 2011;Mitch et al, 2011). However, activity after p.o.…”

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…On the analgesic route of pain circuits, however, not only µ opioid receptors but also κ-receptors appear to be of great relevance not only in relays of the spinothalamic tract conveying signals to higher centers but also as potential modulators of dopamine release in cortical and subcortical brain areas [240]. Most auspicious approach for κ receptor ligands was described in 2003 by Thomas et al [104] [241].…”

“…Efforts to improve high throughput screening and hit refinement strategies give rise for expectations of further candidate structures for potential κ subtype specific PET tracers [240]. The most interesting non-peptide receptor ligand with a role in vascular and inflammatory processes involved in pain circuits appears to be the CGRP antagonist MK4232 (14) evaluated by the group of Bell and Hostetler [60] [153].…”