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

Publication ,  Journal Article
Slosky, LM; Bai, Y; Toth, K; Ray, C; Rochelle, LK; Badea, A; Chandrasekhar, R; Pogorelov, VM; Abraham, DM; Atluri, N; Peddibhotla, S; Yuan, H ...
Published in: Cell
June 11, 2020

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.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 11, 2020

Volume

181

Issue

6

Start / End Page

1364 / 1379.e14

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Small Molecule Libraries
  • Signal Transduction
  • Receptors, Neurotensin
  • Receptors, G-Protein-Coupled
  • Models, Animal
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
 

Citation

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Slosky, L. M., Bai, Y., Toth, K., Ray, C., Rochelle, L. K., Badea, A., … Caron, M. G. (2020). β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors. Cell, 181(6), 1364-1379.e14. https://doi.org/10.1016/j.cell.2020.04.053
Slosky, Lauren M., Yushi Bai, Krisztian Toth, Caroline Ray, Lauren K. Rochelle, Alexandra Badea, Rahul Chandrasekhar, et al. “β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.Cell 181, no. 6 (June 11, 2020): 1364-1379.e14. https://doi.org/10.1016/j.cell.2020.04.053.
Slosky LM, Bai Y, Toth K, Ray C, Rochelle LK, Badea A, et al. β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors. Cell. 2020 Jun 11;181(6):1364-1379.e14.
Slosky, Lauren M., et al. “β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.Cell, vol. 181, no. 6, June 2020, pp. 1364-1379.e14. Pubmed, doi:10.1016/j.cell.2020.04.053.
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. β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors. Cell. 2020 Jun 11;181(6):1364-1379.e14.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 11, 2020

Volume

181

Issue

6

Start / End Page

1364 / 1379.e14

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Small Molecule Libraries
  • Signal Transduction
  • Receptors, Neurotensin
  • Receptors, G-Protein-Coupled
  • Models, Animal
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans