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SBI-553 Sale

目录号 : GC38847

A β-arrestin-biased positive allosteric modulator of NTSR1

SBI-553 Chemical Structure

Cas No.:1849603-72-0

规格 价格 库存 购买数量
1mg
¥864.00
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5mg
¥2,520.00
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10mg
¥4,230.00
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25mg
¥7,560.00
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50mg
¥11,700.00
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100mg
¥16,200.00
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500mg 待询 待询

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产品描述

SBI-553 is a β-arrestin-biased positive allosteric modulator (PAM) of neurotensin receptor 1 (NTSR1).1 It binds to NSTR1 and increases neurotensin-1 affinity for NSTR1 in HEK293 cells expressing the human receptor when used at concentrations ranging from 0.01 to 10 ?M. SBI-553 (0.03-30 ?M) induces β-arrestin recruitment and NTSR1 internalization without stimulating Gq protein activation, 1,4,5-triphosphate (IP3) generation, or calcium mobilization in cell-based assays. In vivo, SBI-553 (12 mg/kg, i.p.) attenuates cocaine- or methamphetamine-induced hyperlocomotion in wild-type but not β-arrestin-2 knockout mice. It also reduces cocaine self-administration in mice.

1.Slosky, L.M., Bai, Y., Toth, K., et al.β-Arrestin-biased allosteric modulator of NTSR1 selectively attenuates addictive behaviorsCell181(6)1364-1379.e1314(2020)

Chemical Properties

Cas No. 1849603-72-0 SDF
Canonical SMILES CN(C1=CC2=C(N=C(N=C2C=C1)C3(CC3)F)N4CCC(CC4)C5=C(C=CC=C5)OC)CCO
分子式 C26H31FN4O2 分子量 450.55
溶解度 DMSO: 62.5 mg/mL (138.72 mM) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.2195 mL 11.0975 mL 22.1951 mL
5 mM 0.4439 mL 2.2195 mL 4.439 mL
10 mM 0.222 mL 1.1098 mL 2.2195 mL
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Research Update

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

Cell 2020 Jun 11;181(6):1364-1379.e14.PMID:32470395DOI:10.1016/j.cell.2020.04.053.

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.

Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

Biochemistry 2023 Apr 4;62(7):1233-1248.PMID:36917754DOI:10.1021/acs.biochem.3c00029.

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1.

Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators

J Med Chem 2019 Sep 12;62(17):8357-8363.PMID:31390201DOI:10.1021/acs.jmedchem.9b00340.

Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.