Synthesis of cannabidiol dimers as potential agents to treat neurological disorders

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The COVID pandemic has worsened stress, anxiety, and depression in the US population. Current FDA approved therapeutics for these ailments are only effective in subpopulations, and it is very common for patients to have to attempt multiple regimens to find one that works. Not surprisingly, patients continue seeking alternative remedies for self-treatment, e.g., cannabis. However, regardless of the legalization of cannabis in many states and its widespread usage for these purposes, cannabis is a diverse mixture of hundreds of compounds that widely vary in amount depending on the cannabis source. One active component of cannabis, cannabidiol (CBD), has been individually studied for its medicinal activity. Epidiolex®, a highly purified form of CBD, is FDA approved to treat rare forms of epilepsy. The issue is that CBD – in its natural form – is a non-specific (poly-pharmacological) agent. CBD weakly activates several receptors of the following classes: cannabinoid, opioid, serotonin (5-HT1A, 5-HT2A), orphan-GPR55, adenosine, and TRP receptors, among others. It remains unclear which receptor(s) and signaling pathway(s) are crucial for the positive benefits of CBD. Our long-term goal is to identify and expand novel therapeutics with defined, specific mechanisms of action for neurological/mental disorders. In this light, the overall objective in this application is to create novel CBD dimers that are proposed to be specific to cannabinoid or serotonin receptors. We will assess the hypothesis that CBD homo/heterodimers will enhance the selective binding to cannabinoid and serotonin receptors through bivalent or bitopic binding on dimerreceptors or a single receptor on two sites, respectively. Upon generation of our CBD homo/heterodimer library, we will evaluate their selectivity for the above receptors, and we will also evaluate dimers in a psychoactive receptor panel (NIMH-PDSP). This will position us to build key preliminary data for a competitive NIH application. Development of these novel dimers as chemical biology probes will elucidate the interactions of CBD with serotonin and cannabinoid receptors and the structural details behind these activities. Ultimately, these CBD semisynthetic derivatives have the potential to yield favorable therapeutic indices for the treatment of stress, anxiety, and depression. Results consistent with our hypothesis will have wide-ranging public health implications because of societal interest in CBD despite its poorly understood activities and because of the urgent need for safe, effective therapies. Importantly, if successful, the long-term goal is to move promising compounds into advanced preclinical testing.