Also expressed in various peripheral tissues, the type-1 cannabinoid receptor (CB1R) is the predominant G protein-coupled receptor (GPCR) in brain, where it is responsible for retrograde control of neurotransmitter release. Cellular signaling mediated by CB1R is involved in numerous physiological processes, and pharmacological CB1R modulation is considered a tenable therapeutic approach for diseases ranging from substance-use disorders and glaucoma to metabolic syndrome. Despite the design and synthesis of a variety of bioactive small molecules targeted to the CB1R orthosteric ligand-binding site, the potential of CB1R as a therapeutic GPCR has been largely unrealized due to adverse events associated with typical orthosteric CB1R agonists and antagonists/inverse agonists. Modulation of CB1R-mediated signal transmission by targeting alternative allosteric ligand-binding site(s) on the receptor has garnered interest as a potentially safer and more effective therapeutic modality. This chapter highlights the design and synthesis of novel, pharmacologically active CB1R allosteric modulators and emphasizes how their molecular properties and the positive and negative allosteric control they exert can lead to improved CB1R-targeted pharmacotherapeutics, as well as designer covalent probes that can be used to map CB1R allosteric binding domains and inform structure-based drug design.
Keywords: 7-Transmembrane receptor; Allosteric modulation; Cannabinoid; Cellular signaling; Central nervous system; Covalent probe; G protein-coupled receptor; Ligand bias; Probe dependence; Receptor activation.
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