Chemistry:SBI-553
SBI-553 is an experimental drug that binds to an intracellular pocket of neurotensin receptor 1 (NTSR1).[1] It acts as a β-arrestin biased positive allosteric modulator and changes NTSR1 G protein preference, biasing NTSR1 away from Gq/11 and toward alternative G protein coupling.[2] It has analgesic effects in animal studies, but importantly also reduces addictive behaviors produced by stimulants and μ-opioid receptor agonists in animal models, suggesting it may be useful as a novel agent for pain relief but which lacks the abuse liability of many currently used analgesic drugs, and may even reduce the potential for addiction when used alongside older analgesics.[3][4][1][5]
A closely related derivative, SBI-810, has superior analgesic effects and may be more likely to be developed for clinical applications.[6][7][8]
References
- ↑ 1.0 1.1 "Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator". Biochemistry 62 (7): 1233–1248. April 2023. doi:10.1021/acs.biochem.3c00029. PMID 36917754.
- ↑ "Designing allosteric modulators to change GPCR G protein subtype selectivity". Nature: 1–10. October 2025. doi:10.1038/s41586-025-09643-2. PMID 41125894.
- ↑ "Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators". Journal of Medicinal Chemistry 62 (17): 8357–8363. September 2019. doi:10.1021/acs.jmedchem.9b00340. PMID 31390201.
- ↑ "β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors". Cell 181 (6): 1364–1379.e14. June 2020. doi:10.1016/j.cell.2020.04.053. PMID 32470395.
- ↑ "Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator". Cell Research 35 (4): 284–295. April 2025. doi:10.1038/s41422-025-01095-7. PMID 40118988.
- ↑ "Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain". Cell 188 (16): 4332–4349.e21. 2025. doi:10.1016/j.cell.2025.04.038. PMID 40393456.
- ↑ "Experimental Painkiller Could Outsmart Opioids – Without the High.". Duke University School of Medicine. 19 May 2025. https://medschool.duke.edu/news/experimental-painkiller-could-outsmart-opioids-without-high.
- ↑ "Non-Opioid Compound Shows Acute and Chronic Pain Relief Potential.". Inside Precision Medicine. 20 May 2025. https://www.insideprecisionmedicine.com/topics/translational-research/non-opioid-compound-shows-acute-and-chronic-pain-relief-potential/.
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