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

Journal Article (Journal Article)

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-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.

Full Text

Duke Authors

Cited Authors

  • Peddibhotla, S; Hedrick, MP; Hershberger, P; Maloney, PR; Li, Y; Milewski, M; Gosalia, P; Gray, W; Mehta, A; Sugarman, E; Hood, B; Suyama, E; Nguyen, K; Heynen-Genel, S; Vasile, S; Salaniwal, S; Stonich, D; Su, Y; Mangravita-Novo, A; Vicchiarelli, M; Roth, GP; Smith, LH; Chung, TDY; Hanson, GR; Thomas, JB; Caron, MG; Barak, LS; Pinkerton, AB

Published Date

  • July 20, 2013

Published In

Volume / Issue

  • 4 / 9

Start / End Page

  • 846 - 851

PubMed ID

  • 24611085

Pubmed Central ID

  • PMC3940307

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml400176n


  • eng

Conference Location

  • United States