Grant: Project Grant

The type 1 cannabinoid receptor (CB1R) is present throughout the brain and body. CB1R helps control normal communication between neurons. Because CB1R helps regulate neuron activity, it is considered a potential drug target for the treatment of epilepsy. Despite its potential as a drug target, very few drugs have been developed that work at this receptor to produce a medical benefit. Our previous research has demonstrated the efficacy of CB1R-targeting compounds in models of absence epilepsy and infantile spasms, highlighting their therapeutic potential. Notably, new treatments for temporal lobe epilepsy (TLE) are urgently needed, as early and effective intervention can improve long-term developmental outcomes. CB1R is activated by d9-tetrahydrocannabinol (THC) found in cannabis. However, THC use is associated with intoxication, tolerance, and dependence, limiting its therapeutic utility. To address these challenges, we are developing agonist-positive allosteric modulators (ago-PAMs)-compounds that selectively enhance CB1R activity without inducing psychoactive effects or dependence. We hypothesize that a CB1R ago-PAM can be developed as effective treatment for TLE. Furthermore, ago-PAMs will be used as a critical tool to examine the role CB1R plays in the activity of specific different neuron types. Our research aims to: (1) design, synthesize and screen novel CB1R ago-PAMs with improved safety will maintaining potency; (2) assess and optimize a subset of these ago-PAMs for safety, brain permeability, and duration of action in animal models; and (3) to apply the knowledge gained from goals 1 and 2 to a mouse model of TLE. This study will advance our understanding of CB1R function across different neuronal populations, refine the use of cannabinoid-based therapeutics, and accelerate the development of novel CB1R modulators to address the unmet clinical needs in epilepsy treatment.