Effect of a β-arrestin Biased Neurotensin Receptor 1 Modulator on Dopamine Receptor D1 β-arrestin Recruitment
The development of effective pharmacotherapies for psychostimulant use disorders remains a critical unmet need due to their escalating public health impact. Neurotensin receptor 1 (NTSR1), a G protein-coupled receptor (GPCR), is integral in modulating dopaminergic signaling pathways in the brain, positioning it as a promising therapeutic target for these disorders. As a GPCR, NTSR1 mediates interactions with G-proteins and β-arrestins. Balanced peptide agonists targeting NTSR1 have demonstrated potential efficacy in preclinical addiction models. Still, their progression to clinical use is prevented by adverse on-target effects such as hypotension, hypothermia, and motor impairment. Therefore, we recently developed β-arrestin-biased NTSR1 ligands, exemplified by the compound SBI-553, which selectively attenuates psychostimulant-associated behaviors with methamphetamine and cocaine-induced motor activity. Despite these promising findings, the mechanism underlying its’ action remains incompletely understood. This project aims to determine the effect of NTSR1 co-expression and activation on D1 receptor signaling to elucidate the mechanism by which SBI-553 eliminates on-target side effects. Using HEK293T cells, calcium phosphate transfections, and Bioluminescence Resonance Energy Transfer (BRET) assays, we hope to help identify the molecular mechanisms through which SBI-553 minimizes adverse effects. This research could pave the way for the development of more effective and safer pharmacotherapies for psychostimulant use disorders.