Cannabinoid receptors and their ligands: ligand-ligand and ligand-receptor modeling approaches

The cannabinoid CB1 and CB2 receptors belong to the class A, rhodopsin-like family of GPCRs. Antagonists for each receptor sub-type, as well as four structural classes of agonists that bind to both receptors, have been identified. An extensive amount of structure-activity relationship information (SAR) has been developed for agonists and antagonists that bind at CB1, while the SAR of CB2 ligands is only now emerging in the literature. This chapter focuses both on recent CB1 and CB2 SAR and on the pharmacophores for ligand recognition at the CB1 receptor that have been developed using ligand-ligand or ligand-receptor approaches. In a ligand-ligand approach, the structure of the binding site of the ligand is not directly considered. This approach is an attempt to infer information about the macromolecular binding site, and/or modes of binding interactions from a correlation between experimentally determined biological activities and the structural and electronic features of a series of small molecules. In a ligand-receptor approach, cannabinoid (CB) receptor models are probed for ligand binding sites and binding sites can be screened using energetic criteria, as well as ligand SAR and the CB mutation literature. This chapter discusses the factors that control the quality of the results emanating from each of these approaches and identifies areas of agreement and of disagreement in the existing CB literature. Challenges for future SAR and pharmacophore development are also identified.