SBI-553 (SBI553) is a potent, selective, β-arrestin-biased, brain penetrant neurotensin receptor 1 (NTR1, NTSR1) allosteric modulator with EC50 of 0.34 uM.
SBI-553 had no effect on the potency of NT in the NTR1 high-content (β-arrestin2-GFP) assay.
SBI-553 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 only showed moderate affinity against a range of related and unrelated GPCRs using the same high-content assay format (NTR2, GPR35, GPR55, K-opioid).
SBI-553 (12 mg/kg, i.p.) attenuated basal hyperlocomotion in dopamine transporter knockout (DAT−/−) mice.
SBI-553 showed efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism.
