2017 • Health Sciences
Novel Pharmacotherapy for Treating Alcohol Addiction
Lead Presenter: Angela Sung
Additional Presenters: Ganesh Thakur, Abhijit Kulkarni, Ritesh Tichkule, Robert Laprairie, Eileen Denovan-Wright, Vinod Yaragudri, Anantha Shekhar
PI: Angela Sung, Ganesh Thakur
Alcohol addiction, which causes 2.5 million deaths/year worldwide, is characterized by excessive drinking, development of tolerance, and physical dependence. Excessive alcohol use can cause cardiovascular and psychiatric problems, and increased risk of cancer. Recent preclinical studies indicate a role of endocannabinoid system in alcohol related behavior. Pharmacological manipulation of cannabinoid CB1 receptor (CB1R) function is shown to modulate alcohol drinking behavior in rodents.
A reduction in motivation to drink alcohol and relapse-like drinking behavior has been demonstrated through pharmacological antagonism of CB1R function in rodents. The potential of currently available antagonists/inverse agonists of CB1R to treat alcohol addiction has been limited due to adverse psychiatric effects. Therefore, developments of new therapeutic agents with no/less side effects are an unmet medical need.
Our lab has been developing negative allosteric modulators (NAMs) of the CB1R with an attempt to overcome the clinical limitations of CB1R antagonists/inverse agonists. Through a focused structure-activity relationship study on PSNCBAM-1, a classical NAM of the CB1R, we have identified novel and functionally selective analogs that are devoid of any psychotropic side effects. In this regard, we examined the effect of GAT358, NAM of CB1R on voluntary alcohol consumption in C57BL/6J mice using a ‘‘two-bottle’’ choice paradigm. Our preliminary studies indicate a significant a dose-dependent reduction in alcohol preference in mice treated with GAT358 compared to vehicle treated mice.
This novel class of compounds acting through a unique mechanism (NAM) provides a better approach for managing alcohol dependence and addiction.