Alcohol addiction is a heterogeneous, chronic relapsing disease and remains a signiﬁcant public health concern, accounting for an estimated 3 to 8 percent of all global deaths. Medical treatments for alcoholism, however, are relatively unexplored. Currently only three medications are approved by the U.S. Food and Drug Administration to treat alcoholism. Unfortunately, these drugs are far from adequate; they are sometimes ineffective, and patients often have trouble complying with their treatments.
Our new study, published recently in the Journal of Medicinal Chemistry, suggests that a brain protein, GPR88, is a potential novel drug target to treat alcohol addiction.
At the neurobiological level, alcohol activates multiple primary and secondary molecular targets in the brain, including some involved in reward pathways. When activated, these pathways can cause feelings of pleasure, relaxation, and craving. The GPR88 protein is a recently discovered orphan receptor expressed in the brain reward system.
Orphan means that the native agonist that activates the receptor has yet to be discovered. As such, the functions of GPR88 in physiology and pathology are still largely unknown. Studying orphan receptors is notoriously difficult, because we lack a suitable in vivo probe to elucidate the receptor functions.
Based on previous in vivo studies, we know that subjects lacking GPR88 seek more alcohol than the control subjects. This led us to wonder if a synthetic small-molecule that stimulates GPR88 could reduce alcohol intake.
In this study, RTI researchers have discovered the first potent and selective small-molecule agonist, named RTI-13951-33, of GPR88 that can enter the brain. The study shows that when given RTI-13951-33, the compound caused subjects to self-administer alcohol less frequently and drink less alcohol than controls. Importantly, there were no effects on locomotion and sugar water self-administration, suggesting that RTI-13951-33 had a selective effect for alcohol reinforcement.
We are still at a very early stage in investigating this potential new drug therapy. The next step will be testing the compound in subjects with and without the GPR88 receptor to prove its in vivo on-target effects.
Creating a tool compound to further validate GPR88 as a novel target to treat alcoholism is an exciting development in itself, especially considering the millions of lives that could be improved through a new form of treatment for alcoholism. The study was done in collaboration with UNC-Chapel Hill and McGill University, Canada, and supported by funding from the National Institute of Mental Health and the National Institute on Alcohol Abuse and Alcoholism.