A Duke University-led team of scientists has developed a synthetic molecule that selectively dampens the physiological rewards of cocaine in mice. The molecule, SBI-553, is a neurotensin receptor 1 (NTSR1) G protein-coupled receptor (GPCR) agonist, which in tests in mice reduced the stimulant effects of cocaine, but with fewer side effects than other drugs that target the same receptor. Used to treat mice that were administered with or had access to the stimulant cocaine or methamphetamine, the new molecule calmed drug-induced hyperactivity, dramatically reduced drug self-administration, and altered metabolic responses in the brain’s reward center.

Identification of SBI-553 could help researchers develop a new class of specific drug addiction therapies that have fewer side effects, leading to better patient outcomes. “This type of activity isn’t something we’ve seen before,” said Lawrence Barak, PhD, an associate research professor who has studied GPCRs for decades, and is co-author on the team’s published paper in Cell, which is titled “β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.”

Drug addiction is a global public health concern for which there is “a paucity of effective therapeutics,” the authors wrote. For decades, researchers working on drug abuse and addiction have looked to develop molecules that would activate one specific GPCR, NTSR1, as a way to interrupt the actions of stimulants, and treat cocaine and methamphetamine addictions.

Neurotensin is known to be involved in drug-seeking behavior and food intake in mice. “It regulates the brain’s reward system and motivated behavior,” said senior post-doctoral fellow Lauren Slosky, PhD, who is the lead author on the paper. However, to date, drugs that have been developed to activate NTSR1 have also had severe side effects on blood pressure, body temperature, and motor coordination, which are also controlled by NTSR1. “This was known, but nobody could do anything about it,” said senior author Marc Caron, PhD, the James B. Duke professor of cell biology in the School of Medicine. His work has focused on GPCR signaling involved in disorders like addiction, schizophrenia, Parkinson’s disease, and depression.

When a GPCR is activated by a signaling molecule, it transmits the signal to the inner portion of the cell via interaction with two intracellular proteins, G protein and β-arrestin. Most GPCR drugs in use today indiscriminately activate both G protein and β-arrestin, but sometimes, activating both molecules with the same GPCR can produce dramatically different physiological effects.

Drug developers have been trying to identify compounds that selectively activate only G protein or β-arrestin, because they have the potential to be safer drugs with fewer side effects. In their newly reported research, the Duke researchers described the development of a new class of small molecules that activate β-arrestin selectively, and so separate the desired effects from unwanted effects. “This kind of idea has been kicking around for 20 years or so,” said Caron.

In collaboration with the Sanford Burnham Prebys Medical Discovery Institute, the Duke team screened 400,000 small molecule drugs to see if any of them could stimulate only the NTSR1 β-arrestin response. One small molecule, SBI-553, that emerged from the screen was found to act at a previously unknown site on the NTSR1 receptor and selectively activate β-arrestin without activating the G protein. SBI-553 can bind NTSR1 at the same time as the natural ligand, neurotensin, and promotes neurotensin’s ability to activate β-arrestin, while blocking its ability to activate the G protein.

The neurotransmitter dopamine mediates reward processing and learning by acting at D1 and D2 receptors (D1Rs and D2Rs) in the brain. Mounting evidence suggests that dysregulation of central dopaminergic neurotransmission, particularly through D2R, is a key contributor to the abuse of psychostimulant and opioid drugs. The Duke team’s tests in mice given either cocaine or methamphetamine showed that treatment with SBI-553 calmed the stimulant drug-induced hyperactivity and impacted on the dopamine system’s ability to alter metabolism in the brain’s rewards center.

Further tests in mice that were allowed to self-administer cocaine showed that treatment using SBI-553 slowed down their drug use within 20 minutes to an hour, and reduced the amount of drug they used by more than 80%, compared to a control group of mice. However, while SBI-553, like conventional NTSR1 activators, was found to reduce the amount of cocaine the animals consumed and their associated drug-craving, it did so without the usual side effects of decreased blood pressure and body temperature and motor coordination problems. “Remarkably, SBI-553 shows efficacy in mouse models of psychostimulant abuse without the side effects characteristic of unbiased NTSR1 agonism,” the authors noted. “In sum, our findings reveal a distinctive class of biased allosteric modulators that permit more precise targeting of GPCR-second messenger signaling and identify an agent whose continued development may directly translate to improved clinical outcomes for patients.”

“The current findings suggest that the selective activation of the NTSR1 β-arrestin response is sufficient to produce some of the anti-addiction effects attributed to the NTSR1, but not its effects on blood pressure and body temperature,” added Slosky, who suggested that because NTSR1 is a prototypical GPCR, molecules of this class can now be pursued for other receptors. “This kind of modulator may allow for the fine-tuning of receptor signaling.”

 

 

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