CB 1 allosteric modulators and their therapeutic potential in CNS disorders

CB₁ is the most abundant GPCR found in the mammalian brain. It has garnered considerable attention as a potential therapeutic drug target. CB₁ 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 CB₁ agonists and antagonists/inverse agonists developed to date are primarily used as research tools. No novel synthetic cannabinoids are currently in the clinics 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 CB₁, but with emphasis on the elimination or mitigation of the potential psychiatric adverse effects that are observed by central agonism/antagonism of CB₁. New pharmacological options are being pursued that may avoid these adverse effects while preserving the potential therapeutic benefits of CB₁ modulation. Allosteric modulation of CB₁ is one such approach. In this review, we will summarize and critically analyze both the in vitro characterization and in vivo validation of CB₁ allosteric modulators developed to date, with a focus on CNS therapeutic effects.