title: 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 of32is blocked by the NTR1 antagonist SR142948A in a dose dependent manner. Unlike peptide based NTR1 agonists, compound32has no significant response in a Ca2+mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional Gqcoupled pathway. This bias has distinct biochemical and functional consequences that may lead to physiological advantages. Compound32displays good brain penetration in rodents, and studies examining itsin vivoproperties are underway.
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Satyamaheshwar
authors.initials: S
authors.lastname: Peddibhotla
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hedrick
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hershberger
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Maloney
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Milewski
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Palak
authors.initials: P
authors.lastname: Gosalia
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Gray
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Eliot
authors.initials: E
authors.lastname: Sugarman
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Becky
authors.initials: B
authors.lastname: Hood
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Eigo
authors.initials: E
authors.lastname: Suyama
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heynen-Genel
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Salaniwal
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Stonich
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Arianna
authors.initials: A
authors.lastname: Mangravita-Novo
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Vicchiarelli
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Roth
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, 260 S. Campus Drive, Salt Lake City, UT 84112.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Hanson
authors.affiliation: RTI International, 3040 E Cornwallis Road, Durham, NC 27709, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.affiliation: Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Barak
authors.affiliation: Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
keywords: GPCR; NTR1; SR142948A; agonist; neurotensin; quinazoline; β-arrestin bias