Synthetic molecule suppresses drug cravings with fewer side effects

A new synthetic molecule developed by Duke University scientists selectively reduces the physiological rewards of cocaine in mice. The molecule may also represent a novel class of drugs that is likely to be more specific with less number of side effects when compared to present medications.

The unique molecule was observed to calm the drug-induced hyperactivity of mice, especially in the ones treated with the stimulant methamphetamine or cocaine. The molecule was also found to interfere with the ability of dopamine system to alter the metabolism in the rewards center of the brain.

In mice that were permitted to self-administer cocaine, the treatment reduced the rate of drug intake from 20 minutes to an hour, and also reduced the amount of drug used by the rodents by over 80% when compared to a control group of mice.

G protein-coupled receptors, or GPCRs, are cell surface chemical receptors that are activated by the molecule SBI-553. GPCRs are the target of over 35% of all FDA-approved drugs activated by SBI-553 molecule. (The finding and characterization of GPCRs fetched the 2012 Nobel Prize in chemistry to the team’s Duke collaborator Robert Lefkowitz).

When a signaling molecule triggers a GPCR, the latter sends that signal to the interior part of the cell through interaction with a pair of intracellular proteins—beta-arrestin and G protein.

A majority of GPCR drugs being used today indiscriminately trigger both beta-arrestin and G protein; at times, triggering both molecules with the same type of GPCR can produce radically varying physiological effects.

Drug developers have been attempting to detect compounds that selectively trigger either the beta-arrestin or G protein because they may lead to safer drugs with minimum side effects.

In a study that appeared online on May 28th, 2020, in the Cell journal, the Duke University researchers have reported the development of a new group of small molecules that may enable just that—thus isolating the good effects from the bad.

This kind of idea has been kicking around for 20 years or so,” added Marc Caron, the study’s senior author and the James B. Duke professor of Cell Biology in the School of Medicine.

Caron’s study targeted the GPCR signaling implicated in several disorders like addiction, depression, Parkinson’s disease, and schizophrenia.

For many years, scientists working on drug addiction and drug abuse have tracked molecules that would trigger a specific GPCR known as neurotensin receptor 1 (NTSR1), as a means to disrupt the actions of stimulants and treat methamphetamine and cocaine addictions.

It is known that neurotensin is involved in food intake and drug-seeking behavior in mice.

It regulates the brain’s reward system and motivated behavior.”

Lauren Slosky, Study Lead Author and Senior Post-Doctoral Fellow, Duke University

Yet, to date, the NTSR1-activating drugs have serious side effects for body temperature, motor coordination, and blood pressure because those are also managed by NTSR1.

Caron added, “This was known, but nobody could do anything about it.”

The Duke team, in association with the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, screened 400,000 small molecule drugs to observe if any of them could trigger the NTSR1 beta-arrestin response.

One small molecule, known as SBI-553, that emerged from the screen serves at a formerly unknown site on the NTSR1 and selectively triggers the beta-arrestin without triggering the G protein.

SBI-553 can couple the NTSR1 at the same time as this receptor’s natural activator—a peptide called neurotensin—and it promotes the ability of neurotensin to trigger the beta-arrestin while suppressing its potential to stimulate the G protein.

This type of activity isn’t something we’ve seen before.”

Lawrence Barak, Study Co-Author and Associate Research Professor, Duke University

Barak has analyzed the GPCRs for many years and started the NTSR1 research program at Duke University as well as the large-scale, collaborative screening effort.

It was observed that SBI-553 reduced the amount of cocaine consumed by the animals and their related drug-craving, just like standard NTSR1 activators. However, it did so without the typical side effects of decreased body temperature and decreased blood pressure, as well as motor coordination problems.

The current findings suggest that the selective activation of the NTSR1 beta-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.”

Lauren Slosky, Study Lead Author and Senior Post-Doctoral Fellow, Duke University

Since NTSR1 is a prototypical GPCR, this class of molecules can be pursued for other types of receptors.

This kind of modulator may allow for the fine-tuning of receptor signaling,” Slosky concluded.

Source:
Journal reference:

Slosky, L. M., et al. (2020) β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors. Cell. doi.org/10.1016/j.cell.2020.04.053.

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