Discovery of ML314, a Brain Penetrant Non-Peptidic 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, 32 (ML314), exhibits full agonist behavior against NTR1 (EC₅₀ = 2.0 μM) in the primary assay and selectivity against NTR2. The effect of 32 is blocked by the NTR1 antagonist SR142948A in a dose dependent manner. Unlike peptide based NTR1 agonists, compound 32 has no significant response in a Ca²⁺ mobilization assay and is thus a biased agonist that activates the β-arres

SUBMITTER: Peddibhotla S 

PROVIDER: S-EPMC3940307 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature