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Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor. | LitMetric
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, (), exhibits full agonist behavior against NTR1 (EC = 2.0 μM) in the primary assay and selectivity against NTR2. The effect of is blocked by the NTR1 antagonist SR142948A in a dose dependent manner. Unlike peptide based NTR1 agonists, compound has no significant response in a Ca mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional G coupled pathway. This bias has distinct biochemical and functional consequences that may lead to physiological advantages. Compound displays good brain penetration in rodents, and studies examining its properties are underway.
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