Bioactive Chemical Composition of Cannabis Extracts and Cannabinoid Receptors.

Cannabis is widely used as a therapeutic drug, especially by patients suffering from psychiatric and neurodegenerative diseases. However, the complex interplay between phytocannabinoids and their targets in the human receptome remains largely a mystery, and there have been few investigations into the relationship between the chemical composition of medical cannabis and the corresponding biological activity. In this study, we investigated 59 cannabis samples used by patients for medical reasons. The samples were subjected to extraction (microwave and supercritical carbon dioxide) and chemical analyses, and the resulting extracts were assayed in vitro using the CB1 and CB2 receptors. Using a partial least squares regression analysis, the chemical compositions of the extracts were then correlated to their corresponding cannabinoid receptor activities, thus generating predictive models that describe the receptor potency as a function of major phytocannabinoid content. Using the current dataset, meaningful models for CB1 and CB2 receptor agonism were obtained, and these reveal the insignificant relationships between the major phytocannabinoid content and receptor affinity for CB1 but good correlations between the two at CB2 receptors. These results also explain the anomalies between the receptor activities of pure phytocannabinoids and cannabis extracts. Furthermore, the models for CB1 and CB2 agonism in cannabis extracts predict the cannabinoid receptor activities of individual phytocannabinoids with reasonable accuracy. Here for the first time, we disclose a method to predict the relationship between the chemical composition, including phytocannabinoids, of cannabis extracts and cannabinoid receptor responses.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Extractions of Medical Cannabis Cultivars and the Role of Decarboxylation in Optimal Receptor Responses.

Introduction: Phytocannabinoids, characteristic compounds produced by medical cannabis, interact with cannabinoid (CB) receptors (CB1 and CB2) as well as other receptor systems to exhibit their corresponding pharmacological effects. In their natural form, CBs such as Δ9-tetrahydrocannabinolic acid and cannabidiolic acid are inactive at these receptors, while their decarboxylated forms (Δ9-tetrahydrocannabinol and cannabidiol, respectively) are potent ligands at CB receptors. Thus, extraction and processing of medical cannabis for active constituents are important. Purpose and Methods: Patients consuming medical cannabis often have limited alternative treatment options and in recent years, medical cannabis extracts have been popular as a substitute for dried cannabis plants, despite limited studies on these derivatives. We investigated three disparate cannabis cultivars and compared four chemical extraction methods head to head, viz. Soxhlet, ultrasound-assisted supercritical fluid, and microwave-assisted extractions, for their efficiency. We further characterized the chemical compositions of these extracts. Results: Microwave extraction consistently produced completely decarboxylated phytocannabinoid extracts. Factors such as temperature and exposure time play important roles in the decarboxylation of phytocannabinoids, thereby generating pharmacologically active CBs, and these conditions may differ for each cannabis cultivar. Conclusion: Chemical consistency and potency due to active compounds are in turn important in producing consistent and reliable medical cannabis extracts and their derivatives. These processes must be subject to higher levels of scientific rigor as the patient population around the world are seeking the help of such extracts for various clinical conditions, and as medical cannabis industry is receiving acceptance in various countries.