2 research outputs found
Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy
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 (IC<sub>50</sub> < 120 nM) or agonists
of high binding affinity (<i>K</i><sub>i</sub> < 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
Discovery of ML314, a Brain Penetrant Nonpeptidic β‑Arrestin Biased Agonist of the Neurotensin NTR1 Receptor
The neurotensin 1 receptor (NTR1) is an important therapeutic target
for a range of disease states including addiction. A high-throughput
screening campaign, followed by medicinal chemistry optimization,
led to the discovery of a nonpeptidic β-arrestin biased agonist
for NTR1. The lead compound, 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)quinazoline, <b>32</b> (ML314), exhibits full agonist behavior against NTR1 (EC<sub>50</sub> = 2.0 μM) in the primary assay and selectivity against
NTR2. The effect of <b>32</b> is blocked by the NTR1 antagonist
SR142948A in a dose-dependent manner. Unlike peptide-based NTR1 agonists,
compound <b>32</b> has no significant response in a Ca<sup>2+</sup> mobilization assay and is thus a biased agonist that activates the
β-arrestin pathway rather than the traditional G<sub><i>q</i></sub> coupled pathway. This bias has distinct biochemical
and functional consequences that may lead to physiological advantages.
Compound <b>32</b> displays good brain penetration in rodents,
and studies examining its in vivo properties are underway