Discovery of Selective Cannabinoid CB₂ Receptor Agonists by High-Throughput Screening

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB₁ and CB₂) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB₁ that are enriched in the CNS. CB₂, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB₂-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB₁ activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB₂. Although no CB₂ PAMs were identified, 167 CB₂ agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB₂ versus CB₁. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.