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

作者：Peddibhotla Satyamaheshwar; Hedrick Michael P; Hershberger Paul; Maloney Patrick R; Li Yujie; Milewski Monika; Gosalia Palak; Gray Wilson; Mehta Alka; Sugarman Eliot; Hood Becky; Suyama Eigo; Nguyen Kevin; Heynen Genel Susanne; Vasile Stefan; Salaniwal Sumeet; Stonich Derek; Su Ying; Mangravita Novo Arianna; Vicchiarelli Michael; Roth Gregory P; Smith Layton H; Chung Thomas D Y; Hanson Glen R; Thomas James B; Caron Marc G; Barak Lawrence S^*

来源：ACS Medicinal Chemistry Letters, 2013, 4(9): 846-851.

DOI：10.1021/ml400176n

• NTR1
• neurotensin
• GPCR
• SR142948A
• quinazoline
• agonist
• beta-arrestin bias
• addiction

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 beta-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 mu M) 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 beta-arrestin pathway rather than the traditional G(q) coupled pathway. This bias has distinct biochemical and functional consequences that may lead to physiological advantages. Compound 32 displays good brain penetration in rodents, and studies examining its in vivo properties are underway.

• 出版日期2013-9