Development of selective cannabinoid receptor 2 agonists for treatment of addiction

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Project Summary America currently faces a dire epidemic of substance use disorders. In 2019, 20.4 million Americans aged 12 or older had a substance use disorder. Approximately 1.6 million suffer from opioid use disorder, which causes more than 136 overdose deaths per day on average. Stimulant abuse is also a significant contributor to this social crisis' extension and severity, with 1 million suffering from methamphetamine use disorder (MUD) and another 1 million from cocaine use disorder. Methamphetamine and cocaine are currently major causes of overdose deaths behind opioids for illicit drugs. Methadone and buprenorphine are widely used treatments for opioid addiction, but there is currently no approved pharmacological treatment for stimulant use disorder (SUD). Thus, there is an urgent need to develop pharmacological interventions for SUD. Medical marijuana has been associated with reduced opioid prescription rates and deaths, and preclinical studies show that cannabinoids affect addictive-like behavior. These effects are believed to be mediated by cannabinoid receptors in the brain. The cannabinoid receptors 1 and 2 (CB1R and CB2R, respectively) are part of the endocannabinoid system and play a crucial role in modulating dopamine (DA) levels in the central nervous system (CNS). Marijuana and nonselective cannabinoids such as THC can activate both CB1R and CB2R. While extensive effort has been invested in understanding the role of CB1R in this DA system, the addictive and psychoactive properties of cannabinoids are also associated with the activation of CB1R. The recent discovery of inhibitory CB2 receptors in the ventral tegmental area (VTA) DA neurons and their inhibitory role in the dopaminergic circuit, leading to reduced DA release in nucleus accumbens (NAc), as well as a receptor modulating glial and microglia function in the CNS, has created a new opportunity for targeting this pathway for therapeutic development. With support from a U18 NIDA pilot grant for the past year, we have successfully identified a lead series of novel chemical entities (NCEs) that display functional selectivity for cyclase over arrestin (i.e., biased) and are also very selective for CB2R with minimal activity for CB1R. Our lead candidate has good oral absorption, brain penetration and, in animal models, reverses the addictive behavior of mice. This proposal aims to further optimize our lead compound as a preclinical/clinical candidate for the treatment of MUD. While displaying excellent selectivity for CB2R over CB1R, our lead compound has residual arrestin activity and needs further PK optimization. We have put together a panel of multidisciplinary experts covering CNS pharmacology, medicinal chemistry, biology, and preclinical and clinical addiction medicine and psychiatry to further support the development of this class of compounds with the help of the Blueprint Neurotherapeutics Network (BPN) before testing in humans.