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The endocannabinoid system is a complex network of lipids, G protein-coupled receptors (GPCRs), and metabolic enzymes and plays a major role in modulating key physiological processes, including nociception, inflammation, and metabolism. The type-1 cannabinoid receptor (CB1) holds great promise for treating CNS and metabolic disorders, pain and glaucoma. The CB1 receptor shows multiple activation mechanisms and it can signal through distinct pathways each of which potentially exhibiting different physiological outcomes. Naturally occurring compounds from Cannabis sativa (phytocannabinoids) and their synthetic derivatives (classical/non-classical cannabinoids), endogenous ligands (endocannabinoids) and their synthetic derivatives, and synthetic compounds of other chemical structures were developed as agonists of the CB1 receptor to promote its signalling. Also, ligands that inhibit the activation of the CB1 receptor have been shown to hold great promise in the clinical setting. This chapter summarizes the diverse panel of ligands that target the CB1 receptor and highlights their use as probes for investigating the modulation of the receptor's activation both in vitro and in vivo.

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