Inature small molecule neurotensin receptor 1 (ntsr1) agonists have been used as potential therapies for mental disorders (including drug addiction) for more than 40 years.
however, clinical development of ntsr1 agonists has been excluded due to serious side effects.
ntsr1 is a G protein coupled receptor (GPCR), which signals through the classic activation of G protein and binds with β - arrestin to mediate different cell signal transduction events.
on May 28, 2020, Lauren M. slosky et al. Published a research paper entitled "β - arrestin biased allosteric modulator of ntsr1 selectively attenuates additive behaviors" in cell, which characterized the allosteric ntsr1 regulator sbi-553.
this small molecule not only acts as a β - arrestin biased agonist, but also extends β - arrestin to endogenous ligands by selectively antagonizing G-protein signaling.
sbi-553 showed efficacy in animal models of psychostimulant drug abuse, including cocaine self administration, without the side effects of ntsr1 agonist.
these findings suggest that activation of ntsr1g protein and β - arrestin produces discrete and separable physiological effects, thus providing a strategy for the development of safer targeted therapies with more direct pharmacological effects.
in addition, Hitoshi Morikawa et al. Published a review article entitled "biasing neurotensin receptor signaling to arrest psychostatin abuse" online on cell, which systematically reviewed the research: reported that β - arrestin biased neurotensin receptor ligand can reduce drug abuse without causing side effects of G protein signal transduction.
drug addiction is a global public health problem, and there is no effective treatment.
addiction is a chronic recurrent disease characterized by maladjustment of the dopamine system in the midbrain limbic region.
the neurotransmitter dopamine mediates reward process and learning by acting on D1 and D2 receptors (D1R and D2R).
more and more evidence suggests that central dopaminergic neurotransmission disorder, especially through D2R, is the key cause of abuse of psychostimulants and opioids.
anatomical and functional data indicate that pharmacologically targeting neuropeptide neurotensin (NTS) and its high affinity G protein coupled receptor (GPCR) ntsr1 can restore steady-state dopamine signal transduction.
in fact, ntsr1 peptide agonists directly antagonize classic effects (e.g., hyperactivity, neurotoxicity, psychotic episodes, and cognitive impairment) associated with the abuse of mental stimulants.
although the exact mechanism of these effects is unclear, ntsr1 inhibits dopamine signaling through its antagonistic function and postulated physical interaction with D2R.
in addition to regulating central dopaminergic transmission, ntsr1 also regulates basic physiological output, including body temperature, blood pressure and motor control.
therefore, addiction therapy combined with ntsr1 may have serious dose limiting side effects, including hypotension, hypothermia and dyskinesia.
in order to overcome this treatment problem, it is necessary to understand the mechanism of how ntsr1 mediates multiple physiological effects, and identify drugs that tend to promote one effect and regulate dopamine signal transduction.
Article pattern (from cell) as GPCR, ntsr1 sends out signals through classic activation of G protein, and makes β - arrestin protein participate in different cell signal transduction events.
these two kinds of β - arrestin, β - arrestin1 and β - arrestin2 are intracellular regulators of GPCR transport and desensitization. Recently, they have been identified as independent mediators of GPCR signal transduction. It has been found that G protein and β - arrestin signal transduction mediate different cellular and physiological functions.
preclinical data have demonstrated the ability of β - arrestin2 to regulate rodent addiction related behaviors, while human genetic results have demonstrated this effect, and the use of β - arrestin in methamphetamine, nicotine and opioids, especially β - arrestin2, is impaired.
in view of the evidence that β - arrestin2 plays a role in addiction, the researchers started the ntsr1 screening program based on β - arrestin.
this program identified a series of small molecule ntsr1 ligands, which showed β - arrestin bias and activity in vivo.
however, their low potency, poor water solubility and poor pharmacokinetics in rodents limit their use as tool compounds.
the pharmacochemical optimization of active scaffolds has led to the current oral brain permeability lead compound sbi-0654553 (sbi-553).
in this study, it was proved that sbi-553 is a β - arrestin biased allosteric ntsr1 activator, which can make NTS occupied ntsr1 shift to Gq protein signal transduction and recruit to β - arrestin.
sbi-553 not only has the effect of β - arrestin biased ligand, but also has the functional selectivity to nts, so it has more direct pharmacological effect in vivo.
it is worth noting that sbi-553 treatment can reduce the behavior associated with psychostimulants without the occurrence of hypothermia and hypotension.
these findings suggest that ntsr1g protein and β - arrestin signal transduction mediate different physiological functions, and identify a unique class of compounds that can transform the boundaries between agonists and antagonists, activators and modulators.