Development of Novel Type 1 Cannabinoid Receptor Positive Allosteric Modulators for Infantile Spasms

The type 1 cannabinoid receptor (CB1R) is present throughout the brain and body. CB1R helps control appetite, mood, pain, and movement. Because CB1R helps control many important bodily processes, it is considered a potential drug target for the treatment of addiction, anxiety, pain, and epilepsy. Despite its potential as a drug target, very few drugs have been developed that work at this receptor to produce a medical benefit. Infantile Spasms syndrome is a newborn and paediatric epilepsy. High-dose corticosteroids or vigabatrin are typical treatments, but spasms persist in half of treated children and these drugs have significant side effects. New treatments are needed because early successful treatment may result in improved long-term developmental outcomes. Emerging clinical data suggest some cannabinoids have anti-seizure effects. CB1R is activated by d9-tetrahydrocannabinol (THC) found in Cannabis and the body's own cannabinoids. THC use produces intoxication and repeated use can result in tolerance and dependence. We are developing new compounds, called positive allosteric modulators, that increase CB1R's response to the body's own cannabinoids, but cannot activate CB1R alone. Our compounds will not produce the intoxication, tolerance, or dependence associated with other cannabinoids. We hypothesize that a CB1R positive allosteric modulator can be developed as a treatment for Infantile Spasms. The goals of our research are: (1) to develop allosteric modulators of CB1R that alter the body's response to its own cannabinoids, (2) test those modulators in animal models, and (3) to apply the knowledge gained from goals 1 and 2 to paediatric epilepsy in rodent models of Infantile Spasms. This research will improve our understanding of CB1R, inform our use of cannabinoids as medicine, and lead to the development of new drug compounds for a devastating childhood disease with an unmet clinical need.