Discovery of ML314, a Brain Penetrant Nonpeptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor

Abstract

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 non-peptidic 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> (<b>ML314</b>), exhibits full agonist behavior against NTR1 (EC₅₀ = 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 Ca²⁺ mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional G _<i>q</i> 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 <i>in vivo</i> properties are underway.