CB allosteric modulators and their therapeutic potential in CNS disorders.

CB is the most abundant GPCR found in the mammalian brain. It has garnered considerable attention as a potential therapeutic drug target. CB is involved in a wide range of physiological and psychiatric processes and has the potential to be targeted in a wide range of disease states. However, most of the selective and non-selective synthetic CB agonists and antagonists/inverse agonists developed to date are primarily used as research tools. No novel synthetic cannabinoids are currently in the clinic for use in psychiatric illness; synthetic analogues of the phytocannabinoid THC are on the market to treat nausea and vomiting caused by cancer chemotherapy, along with off-label use for pain. Novel strategies are being explored to target CB, but with emphasis on the elimination or mitigation of the potential psychiatric adverse effects that are observed by central agonism/antagonism of CB. New pharmacological options are being pursued that may avoid these adverse effects while preserving the potential therapeutic benefits of CB modulation. Allosteric modulation of CB is one such approach. In this review, we will summarize and critically analyze both the in vitro characterization and in vivo validation of CB allosteric modulators developed to date, with a focus on CNS therapeutic effects.