Details

Autor(en) / Beteiligte

• Slosky, Lauren M.
• Bai, Yushi
• Toth, Krisztian
• Ray, Caroline
• Rochelle, Lauren K.
• Badea, Alexandra
• Chandrasekhar, Rahul
• Pogorelov, Vladimir M.
• Abraham, Dennis M.
• Atluri, Namratha
• Peddibhotla, Satyamaheshwar
• Hedrick, Michael P.
• Hershberger, Paul
• Maloney, Patrick
• Yuan, Hong
• Li, Zibo
• Wetsel, William C.
• Pinkerton, Anthony B.
• Barak, Lawrence S.
• Caron, Marc G.

Titel

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

Ist Teil von

• Cell, 2020-06, Vol.181 (6), p.1364-1379.e14

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •The small molecule SBI-553 typifies a distinctive class of GPCR ligands•SBI-553 is a β-arrestin-biased allosteric modulator of neurotensin receptor 1 (NTSR1)•SBI-553 reduces stimulant effects without the side effects of unbiased NTSR1 agonists•Allosteric targeting of GPCRs will enable the development of superior therapeutics An ago-allosteric modulator that biases neurotensin receptor 1 signaling toward β-arrestin shows promise as a means of treating psychostimulant addictions and avoiding G protein-mediated side effects.