2. Academic Validation
  3. β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors

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

  • Cell. 2020 Jun 11;181(6):1364-1379.e14. doi: 10.1016/j.cell.2020.04.053.
Lauren M Slosky 1,  Yushi Bai 1,  Krisztian Toth 2,  Caroline Ray 1,  Lauren K Rochelle 1,  Alexandra Badea 3,  Rahul Chandrasekhar 1,  Vladimir M Pogorelov 4,  Dennis M Abraham 5,  Namratha Atluri 1,  Satyamaheshwar Peddibhotla 6,  Michael P Hedrick 6,  Paul Hershberger 6,  Patrick Maloney 6,  Hong Yuan 7,  Zibo Li 8,  William C Wetsel 9,  Anthony B Pinkerton 10,  Lawrence S Barak 11,  Marc G Caron 12
Affiliations

Affiliations

  • 1 Department of Cell Biology, Duke University, Durham, NC 27710, USA.
  • 2 Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Pharmaceutical Sciences, Campbell University, Buies Creek, NC 27506, USA.
  • 3 Departments of Radiology and Neurology, Brain Imaging and Analysis Center, Duke University, Durham, NC 27710, USA.
  • 4 Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, USA.
  • 5 Department of Medicine, Division of Cardiology and Duke Cardiovascular Physiology Core, Duke University, Durham, NC 27710, USA.
  • 6 Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 7 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 8 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Linebarger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 9 Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, USA; Department of Neurobiology, Duke University, Durham, NC 27710, USA.
  • 10 Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 11 Department of Cell Biology, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
  • 12 Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Neurobiology, Duke University, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 32470395 DOI: 10.1016/j.cell.2020.04.053
Abstract

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.

Keywords

G protein-coupled recpetor; GPCR; NTSR1; PET; addiction; allosteric modulator; cocaine; dopamine; methamphetamine; neurotensin receptor 1; positron emission tomography; self-administration; β-arrestin.

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