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

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

  • ACS Med Chem Lett. 2013 Jul 20;4(9):846-851. doi: 10.1021/ml400176n.
Satyamaheshwar Peddibhotla 1,  Michael P Hedrick 2,  Paul Hershberger 1,  Patrick R Maloney 1,  Yujie Li 2,  Monika Milewski 2,  Palak Gosalia 2,  Wilson Gray 2,  Alka Mehta 1,  Eliot Sugarman 1,  Becky Hood 1,  Eigo Suyama 1,  Kevin Nguyen 1,  Susanne Heynen-Genel 2,  Stefan Vasile 1,  Sumeet Salaniwal 2,  Derek Stonich 2,  Ying Su 2,  Arianna Mangravita-Novo 1,  Michael Vicchiarelli 1,  Gregory P Roth 1,  Layton H Smith 1,  Thomas D Y Chung 2,  Glen R Hanson 3,  James B Thomas 4,  Marc G Caron 5,  Lawrence S Barak 5,  Anthony B Pinkerton 2
Affiliations

Affiliations

  • 1 Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
  • 2 Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
  • 3 Department of Pharmacology and Toxicology, University of Utah, 260 S. Campus Drive, Salt Lake City, UT 84112.
  • 4 RTI International, 3040 E Cornwallis Road, Durham, NC 27709, USA.
  • 5 Duke University Medical Center, Durham, NC 27710, USA.
PMID: 24611085 DOI: 10.1021/ml400176n
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-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.

Keywords

GPCR; NTR1; SR142948A; agonist; neurotensin; quinazoline; β-arrestin bias.

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