Duke University researchers have developed a synthetic molecule (SBI-553) that selectively dampens the physiological rewards of cocaine. In mice that were allowed to self-administer cocaine, the treatment slowed drug use by more than 80%. The study was published today in Cell.
SBI-553 activates GPCRs, cell surface receptors that are the target of more than 35% of FDA-approved drugs. GPCRs transmit signals to the inner portion of the cell via interaction with two intracellular proteins: G protein and beta-arrestin. Most GPCR drugs in use today indiscriminately activate both G protein and beta-arrestin, but the new study reports the development of a new class of small molecules that may allow for the selective activation of just one of these proteins, potentially limiting drug side effects.
For decades, researchers working on drug abuse and addiction have pursued molecules that would activate one specific GPCR called neurotensin receptor 1 (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,” says first author Lauren Slosky.
But so far, the drugs that activate NTSR1 have severe side effects for blood pressure, body temperature, and motor coordination, because those are also controlled by NTSR1. “This was known, but nobody could do anything about it,” says senior author Marc Caron.
The researchers screened 400,000 small molecule drugs to see if any of them could stimulate the NTSR1 beta-arrestin response. They found the small molecule SBI-553, which acts at a previously unknown site on the NTSR1 and selectively activates the beta-arrestin without activating the G protein. SBI-553 can bind the NTSR1 at the same time as this receptor’s natural activator, a peptide known as neurotensin, and it promotes neurotensin’s ability to activate beta-arrestin while blocking its ability to activate the G protein.
Like conventional NTSR1 activators, SBI-553 was found to reduce the amount of cocaine the animals consumed and their associated drug craving. But it did so without the usual side effects of decreased blood pressure and body temperature and motor coordination problems.
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,” Slosky says.