ReviewCannabinergic ligands
Introduction
Marijuana (Cannabis sativa) is one of the oldest drugs of abuse, but its medicinal value has also been known for many years. It was the identification of Δ9-tetrahydrocannabinol (Δ9-THC) as the major psychoactive component in cannabis as well as its chemical synthesis that began a new era for synthetic cannabinoids as pharmacological agents (Gaoni and Mechoulam, 1964). The next milestone in cannabinoid research was the discovery that cannabinoids produce most of their biochemical and pharmacological effects by interacting with CB1 and CB2 cannabinoid receptors, both of which are G-protein coupled membrane-bound functional proteins (Matsuda et al., 1990, Gerard et al., 1991). CB1 is found in the central nervous system (CNS) and in a variety of other organs, including the heart, vascular endothelium, uterus, vas deferens, testis and small intestine (Herkenham et al., 1990, Breivogel and Childers, 1998, Gatley et al., 1998, Schuel et al., 1999). Conversely, the CB2 receptor appears to be associated exclusively with the immune system and is found in the periphery of the spleen and other cells associated with immunochemical functions, but not in the brain (Munro et al., 1993). The subsequent discovery of the endogenous cannabinoids (endocannabinoids) arachidonoylethanolamide (anandamide) (Devane et al., 1992, Hanus et al., 1993), 2-arachidonoyl glycerol (2-AG) (Mechoulam et al., 1995, Mechoulam et al., 1998) and very recently, a third 2-arachidonyl ether (noladin ether) (Hanus et al., 2001), has led to a better understanding of the physiological and biochemical role of the endocannabinoid system.
These endogenous cannabinoids have revealed the existence of three additional proteins, fatty acid amide hydrolase (FAAH), monoacylglycerol (MAG) lipase and the anandamide transporter (AT), which are involved in the metabolism of endocannabinoids (Di Marzo et al., 1998, Khanolkar and Makriyannis, 1999).
Pharmacological studies, that will further elucidate the role of the endocannabinoid system in physiological and disease states, are dependent on the availability of selective agents that interact specifically and selectively with each of the endocannabinoid proteins and in turn, either activate or inhibit them. Therefore, structure–activity relationship (SAR) studies on each of these targets and the subsequent identification of differences in their ligand recognition are of great significance, as they can lead to the development of selective cannabinergic agents. In addition, such studies may lead to the development of new therapeutic agents that act through the endocannabinoid system. To date, four cannabinoid system proteins including the CB1 and CB2 receptors, fatty acid amide hydrolase and the anandamide transporter, have received considerable attention and show great promise as potential targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression and motor disorders (Goutopoulos and Makriyannis, 2002, Musty, 2002).
During the last decade, numerous selective ligands for each of the cannabinergic proteins were designed and synthesized (Goutopoulos and Makriyannis, 2002). Many of these agents serve as important molecular probes, providing structural information about receptor binding sites, as well as serving as pharmacological tools for obtaining information about the role of each of these targets in physiological and disease states (Khanolkar et al., 2000). The extensive exploration and structure activity studies of cannabinoid pharmacology have resulted in the development of more structurally diverse classes of cannabimimetic ligands. Currently, six major classes of cannabimimetics have been identified: (1) classical cannabinoids; (2) non-classical and hybrid cannabinoids; (3) aminoalkylindoles; (4) arachidonoylethanolamides; (5) biarylpyrazoles; and (6) 2-arachidonoylglycerols. This review will focus on the important cannabinoid probes categorized based on their pharmacological properties and will highlight their therapeutic potential.
Section snippets
Cannabinergic ligand classifications
Both CB1 and CB2 receptors are members of the superfamily of the seven transmembrane receptors that transduce intracellular signals via heterotrimeric GTP-binding proteins. The CB2 receptor shows 44% identity to the total CB1 receptor and 68% identity within the transmembrane regions (Munro et al., 1993). The central distribution pattern of the CB1 receptor is heterogeneous and accounts for several prominent pharmacological properties of CB1 receptor agonists, for example their ability to
Acknowledgements
Research in the A. Makriyannis laboratory is funded by the National Institutes on Drug Abuse (DA9158, DA03801 and DA07215).
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2018, Brain Research BulletinCitation Excerpt :The endocannabinoid system (ECS), which comprises the cannabinoid CB1, CB2 receptors, the endocannabinoids and their synthetic and metabolizing enzymes, is involved in the regulation of numerous physiological processes. The two main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) may play a role in these regulatory mechanisms either as neurotransmitters or neuromodulators (Palmer et al., 2002), and dysregulation of the ECS has been demonstrated in several diseases (for review see: Pacher and Kunos, 2013). Besides endocannabinoids other naturally occurring cannabinoids are the plant-derived phytocannabinoids.