Minireview: From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation

Abstract

The effects of cannabinoids have been known for centuries and over the past several decades two G protein-coupled receptors, CB1 and CB2, that are responsible for their activity have been identified. Endogenous lipid-derived cannabinergic agents have been found, biosynthetic and catabolic machinery has been characterized, and synthetic agents have been designed to modulate these receptors. Selective agents including agonists, antagonists, inverse agonists, and novel allosteric modulators targeting either CB1 or CB2 have been developed to inhibit or augment their basal tone. As a result, the role these receptors play in human physiology and their potential therapeutic applications in disease states are being elucidated. The CB1 receptor, although ubiquitous, is densely expressed in the brain, and CB2 is largely found on cells of immune origin. This minireview highlights the role of CB1 in excitotoxic assaults in the brain and its potential to limit addiction liability. In addition, it will examine the relationship between receptor activity and stimulation of insulin release from pancreatic β-cells, insulin resistance, and feeding behavior leading toward obesity. The roles of CB2 in the neuropathology of amyotrophic lateral sclerosis and in the central manifestations of chronic HIV infection potentially converge at inflammatory cell activation, thereby providing an opportunity for intervention. Last, CB2 modulation is discussed in the context of an experimental model of postmenopausal osteoporosis. Achieving exquisite receptor selectivity and elucidating the mechanisms underlying receptor inhibition and activation will be essential for the development of the next generation of cannabinergic-based therapeutic agents.

Figure 1.

Representative ligands that modulate the CB1 and CB2 receptors, including the natural product Δ⁹-THC, endogenous lipid-derived agonists AEA and 2-AG, and synthetic agonists CP55940 and WIN55212-2. CB1-selective ligands include SR141716A, AM251, and AM6545 (all inverse agonists), whereas the CB2-selective molecules are represented by AM630 (inverse agonist), SR144528 (inverse agonist), AM1241 (agonist), and HU308 (agonist).

Figure 2.

Cannabinoid receptor modulation has an impact on a host of cellular pathways. Activation of CB1 or CB2 receptors results in a release of G protein heterotrimer, which has a negative impact on cellular production of cAMP, activates K⁺_A and K⁺_IR channels, and inhibits Ca²⁺ channels. In addition, activated CB1 or CB2 receptors can recruit β-arrestin to the plasma membrane. When stimulated, CB1 has the ability to activate MAPK, phosphatidylinositol 3-kinase, and FAK, among other pathways, and although less is known about CB2, it is also capable of activating MAPK.

Figure 3.

Allosteric ligands for CB1 are capable of modulating orthosteric ligand (agonist) activity. A, Schematic representation of the CB1 receptor TMD bundle illustrating the topographic distinction between allosteric and orthosteric binding sites. B, Structures of representative allosteric modulators for CB1 including ORG27569, PSNCBAM-1, lipoxin A4, RTI371, and LDK1256 and LDK1258 (also referred to as compounds 12d and 12f from Ref. 46).

Figure 4.

Cannabinoid receptors as therapeutic targets for human disease. Receptor activation (shown in green) and blockade (shown in red) have the ability to alter physiology both in rodent models of disease and in humans. A, CB1 receptor activation has been explored as a means to protect against excitotoxic insult in the brain and has been shown to occur during hyperglycemia, resulting in insulin release from the pancreas. Conversely, CB1 blockade has been investigated as a means to reduce addiction liability in rodent models and has been demonstrated to decrease food intake and improve surrogate markers of metabolic disease (liver and pancreas) while producing weight loss observed both in rodents and in human clinical trials. B, CB2 activation has been explored as a means to delay progression of ALS, selectively target HIV-infected microglial cells in the CNS, and inhibit HIV reverse transcriptase as well as restore the balance between osteoblasts and osteoclasts in a rodent model of postmenopausal osteoporosis while increasing trabecular bone mass.