β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.

Published

Journal Article

Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their severe side effects. NTSR1, a G protein-coupled receptor (GPCR), signals through the canonical activation of G proteins and engages β-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a β-arrestin-biased agonist but also extends profound β-arrestin bias to the endogenous ligand by selectively antagonizing G protein signaling. SBI-553 shows efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism. These findings indicate that NTSR1 G protein and β-arrestin activation produce discrete and separable physiological effects, thus providing a strategy to develop safer GPCR-targeting therapeutics with more directed pharmacological action.

Full Text

Duke Authors

Cited Authors

  • Slosky, LM; Bai, Y; Toth, K; Ray, C; Rochelle, LK; Badea, A; Chandrasekhar, R; Pogorelov, VM; Abraham, DM; Atluri, N; Peddibhotla, S; Hedrick, MP; Hershberger, P; Maloney, P; Yuan, H; Li, Z; Wetsel, WC; Pinkerton, AB; Barak, LS; Caron, MG

Published Date

  • June 11, 2020

Published In

Volume / Issue

  • 181 / 6

Start / End Page

  • 1364 - 1379.e14

PubMed ID

  • 32470395

Pubmed Central ID

  • 32470395

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2020.04.053

Language

  • eng

Conference Location

  • United States