Endocannabinoids and their receptors as targets for treating metabolic and psychiatric disorders

The CB1 receptor is arguably one of the most abundant GPCRs in the CNS and has long been attractive as a therapeutic target for a wide variety of therapeutic indications including pain, weight gain, emesis and mood disorders. Its cousin, the CB2 receptor, is highly localized in the immune cells regulating immune function and inflammatory pain. Direct acting nonselective agonists, while providing potentially broad therapeutic efficacy, also cause undesirable sedative and hypnotic side effects. New approaches to leverage cannabinoid biology for therapeutic benefit show promise of providing the therapeutic benefits without the buzz.

Introduction

Improving the medicinal properties of plant-derived cannabinoids has long been a sought after goal of early alchemists and also of modern day pharmaceutical discovery groups. Although marijuana contains a complex mixture of over 50 bioactive cannabinoids, the pharmacology has focused primarily on its major active principle, Δ⁹-tetrahydrocannabinol (Δ⁹-THC)(Fig. 1). A binding site for Δ⁹-THC was discovered in brain extracts nearly two decades ago [1], and it is now known that the cannabinoid GPCR receptor (G protein coupled receptor) family consists of two receptor subtypes (CB1 and CB2) [2]. The CB1 receptor (cannabinoid CB1 receptor) is Gi-coupled, primarily inhibitory in function, and abundantly expressed in the CNS, particularly in the cortex and basal forebrain areas [3]. The CB2 receptor (cannabinoid CB2 receptor) is also G-coupled, but is predominantly expressed in peripheral and central immune cells [4], with low CNS abundance [5]. Agonists of the CB1 receptor stimulate feeding and have anti-emetic and analgesic properties. Direct application to the eyes reduces intraocular pressure in glaucoma, and systemic exposure alleviates muscle spasms in multiple sclerosis. Antagonizing the CB1 receptor reduces craving for palliative food and normalizes dislipidemias associated with metabolic syndrome. Reduction in craving and impulsivity may provide opportunities in substance abuse disorders. CB2 agonism attenuates inflammatory processes and inflammatory pain. The significance of central CB2 receptors has yet to be understood fully, but preliminary studies indicate CB2 receptor upregulation in activated microglia associated with amyloid plaques [6] and possibly regulation of emesis through brainstem localized receptors [7]. The use of CB2 antagonists is more speculative but may be useful in immune deficiency syndromes [8].

Discovery of the cannabinoid receptor genes and proteins provided the necessary tools to search for endogenous ligands. Based on the physical properties of the established pharmacology, the endogenous ligand was thought to be very lipophilic in nature. The first endogenous cannabinoid to be discovered, anandamide (N-arachidonoylethanolamine), was in fact a membrane-derived lipid molecule composed of the fatty acid, arachidonic acid, coupled to ethanolamine through an amide linkage. The term endocannabinoid was coined to describe a diverse set of lipid mediators that stimulate the CB1 and CB2 receptors as well as other proteins such as the TRPV-1 calcium channel and PPARα nuclear hormone receptor [9]. Understanding the breadth of endocannabinoid structural diversity as well as the mechanisms of their synthesis and disposal is an active area of research. The field is poised to leverage modern pharmacological methods and mechanistic knowledge to modulate cannabinoid receptors selectively to provide therapeutic benefit while minimizing adverse pharmacological responses.