Alcohol use disorders can have devastating effects on a person’s health, relationships and finances. Yet for some, the feeling they get when taking a drink temporarily outweighs these other concerns. Now, researchers have developed a new drug that could dampen alcohol’s effects on the brain’s “reward system,” causing rats to self-administer the beverage less frequently. They report their results in ACS’ Journal of Medicinal Chemistry.
Once consumed, alcohol enters the brain and interacts with neurotransmitters and their receptors, including some involved in reward-system pathways. When activated, these pathways can cause feelings of pleasure, relaxation and craving. Although alcohol-treatment drugs that interfere with the reward system exist, these drugs are not very effective and can have serious side effects. To develop a better treatment, Chunyang Jin and colleagues focused their efforts on a protein receptor called GPR88 that is found predominantly in reward-related areas of the brain. Previous research on mice genetically engineered to lack GPR88 showed that these animals seek and consume alcohol more than normal mice. This led the researchers to wonder if a drug that stimulates GPR88 could reduce alcohol cravings. They had previously developed a synthetic small molecule that activates GPR88 in vitro; however, this molecule could not effectively cross the blood-brain barrier.
The researchers tweaked the structure of the compound to make it more likely to enter the brain. They arrived at a molecule called RTI-13951-33 that was potent, selective for GPR88 and could cross the blood-brain barrier. When given RTI-13951-33, non-engineered rats drank less alcohol than before they received the drug. In contrast, the rats gave themselves sugar water at the same frequency with or without the drug. The researchers say they are now studying the molecule in both wild-type mice and those that lack the GPR88 receptor to prove that it is specific for that receptor.
This article has been republished from materials provided by the American Chemical Society. Note: material may have been edited for length and content. For further information, please contact the cited source.
Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake. Chunyang Jin, Ann M. Decker, Viren H. Makhijani, Joyce Besheer, Emmanuel Darcq, Brigitte L. Kieffer, and Rangan Maitra. J. Med. Chem., 2018, 61 (15), pp 6748–6758 DOI: 10.1021/acs.jmedchem.8b00566.