Discovery of Selective Cannabinoid CB 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 (CB and CB) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB that are enriched in the CNS. CB, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB 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 CB. Although no CB PAMs were identified, 167 CB agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB versus CB. 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.