Journal
CELL
Volume 181, Issue 6, Pages 1364-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.04.053
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Funding
- Duke Center for In Vivo Microscopy [P41EB01589a, U24CA220245]
- North Carolina Biotechnology Center
- David Pall family part of the Long Island Community Foundation, a division of The New York Community Trust
- UNC Biomedical Research Imaging Center (BRIC) [P30CA016086]
- [F32DA043931]
- [K99DA048970]
- [1K01AG041211]
- [K08HL125905-01]
- [R21/33DA038019]
- [P30DA029925]
- [R37MH073853]
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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 beta-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a beta-arrestin-biased agonist but also extends profound beta-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 beta-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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