The development and therapeutic potential of classical and next-generation cannabinoid ligands

The endogenous cannabinoid system (ECS) is a complex network that plays a crucial role in various physiological processes, and its modulation through cannabinoid ligands has garnered significant interest in pharmacological research. Cannabinoid receptors, primarily CB₁ and CB₂, are G-protein-coupled receptors that can interact with many different types of ligands, including orthosteric agonists and antagonists and allosteric and biased modulators. This review provides an updated perspective on cannabinoid receptor ligand development, beginning with natural ligands such as phytocannabinoids and endocannabinoids. These compounds provided the initial inspiration for the design of the first synthetic classical cannabinoids which were later refined into structurally distinct non-classical cannabinoids. Beyond these traditional orthosteric ligands, we explore the expanding field of allosteric and biased modulators, which offer refined control over receptor signaling and present opportunities to reduce side effects associated with direct receptor activation. We also highlight the significance of covalent ligands and labeled chemical probes in elucidating cannabinoid receptor structure, localization, and function. Advances in imaging and chemoproteomic techniques have further enhanced our ability to visualize receptor dynamics and identify novel interaction partners. Finally, we examine the clinical landscape of cannabinoid-based therapeutics, from approved drugs to ongoing clinical trials, and discuss the remaining challenges and future directions in ECS-targeted drug development. This review aims to provide a comprehensive overview of current trends and emerging strategies in cannabinoid ligand research.