Review
Cannabinergic ligands

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Abstract

The understanding of the pharmacology surrounding the cannabinergic system has seen many advances since the discovery of the CB1 receptor in the mammalian brain and the CB2 receptor in the periphery. Among these advances is the discovery of the endogenous ligands arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol amide (2-AG), which are selective agonists for the CB1 and CB2 receptors, respectively. These endogenous neuromodulators involved in the cannabinergic system are thought to be produced on demand and are metabolized by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAG lipase). Recently, we characterized a reuptake system that facilitates the transport of anandamide across the cell membrane and subsequently developed selective inhibitors of this transport, which have been found to have therapeutic potential as analgesic and peripheral vasodilators. The cannabinergic proteins currently being explored, which include the CB1 and CB2 receptors, FAAH and the anandamide transporter, are excellent targets for the development of therapeutically useful drugs for a range of conditions including pain, loss of appetite, immunosuppression, peripheral vascular disease and motor disorders. As cannabinoid research has progressed, various potent and selective cannabimimetic ligands, targeting these four cannabinoid proteins, have been designed and synthesized. Many of these ligands serve as important molecular probes, providing structural information regarding the binding sites of the cannabinergic proteins, as well as pharmacological tools, which have been playing pivotal roles in research aimed at understanding the biochemical and physiological aspects of the endocannabinoid system. This review will focus on some of the current cannabinergic ligands and probes and their pharmacological and therapeutic potential.

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).

References (87)

  • A. Giuffrida et al.

    Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404

    Eur. J. Pharmacol.

    (2000)
  • S. Gonzalez et al.

    Extrapyramidal and neuroendocrine effects of AM404, an inhibitor of the carrier-mediated transport of anandamide

    Life Sci.

    (1999)
  • A. Goutopoulos et al.

    From cannabis to cannabinergics new therapeutic opportunities

    Pharmacol. Ther.

    (2002)
  • A. Goutopoulos et al.

    Stereochemical selectivity of methanandamides for the CB1 and CB2 cannabinoid receptors and their metabolic stability

    Bioorg. Med. Chem.

    (2001)
  • A.D. Khanolkar et al.

    Structure–activity relationships of anandamide, an endogenous cannabinoid ligand

    Life Sci.

    (1999)
  • A.D. Khanolkar et al.

    Molecular probes for the cannabinoid receptors

    Chem. Phys. Lipids

    (2000)
  • B. Koutek et al.

    Inhibitors of arachidonoyl ethanolamide hydrolysis

    J. Biol. Chem.

    (1994)
  • M. Maccarrone et al.

    Anandamide hydrolysis by human cells in culture and brain

    J. Biol. Chem.

    (1998)
  • A. Makriyannis et al.

    The molecular basis of cannabinoid activity

    Life Sci.

    (1990)
  • S. Maurelli et al.

    Two novel classes of neuroactive fatty acid amides are substrates for mouse neuroblastoma ‘anandamide amidohydrolase’

    FEBS Lett.

    (1995)
  • R. Mechoulam et al.

    Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors

    Biochem. Pharmacol.

    (1995)
  • R. Mechoulam et al.

    Endocannabinoids

    Eur. J. Pharmacol.

    (1998)
  • K.L. Morse et al.

    A novel electrophilic high affinity irreversible probe for the cannabinoid receptor

    Life Sci.

    (1995)
  • R.G. Pertwee

    Pharmacology of cannabinoid CB1 and CB2 receptors

    Pharmacol. Ther.

    (1997)
  • R.G. Pertwee

    Cannabinoid receptors and pain

    Prog. Neurobiol.

    (2001)
  • R.G. Pertwee

    Cannabinoids and multiple sclerosis

    Pharmacol. Ther.

    (2002)
  • R. Pertwee et al.

    Am630, a competitive cannabinoid receptor antagonist

    Life Sci.

    (1995)
  • M.A. Tius et al.

    Conformationally restricted hybrids of CP-55,940 and HHC: stereoselective synthesis and activity

    Tetrahedron

    (1994)
  • M.A. Tius et al.

    Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain

    Life Sci.

    (1995)
  • V. Abadji et al.

    J. Med. Chem.

    (1994)
  • A. Al-Hayani et al.

    Cannabinoid receptor mediated inhibition of excitatory synaptic transmission in the rat hippocampal slice is developmentally regulated

    Br. J. Pharmacol.

    (2000)
  • D. Baker et al.

    Cannabinoids control spasticity and tremor in a multiple sclerosis model

    Nature

    (2000)
  • M.R. Bell et al.

    Antinociceptive (aminoalkyl)indoles

    J. Med. Chem.

    (1991)
  • M. Beltramo et al.

    Functional role of high-affinity anandamide transport, as revealed by selective inhibition

    Science

    (1997)
  • M. Beltramo et al.

    Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor

    J. Neurosci.

    (2000)
  • D.L. Boger et al.

    Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide

    Proc. Natl. Acad. Sci. USA

    (2000)
  • A. Charalambous et al.

    5′-Azido-Δ8-THC: a novel photoaffinity label of the cannabinoid receptor

    J. Med. Chem.

    (1992)
  • D.R. Compton et al.

    The effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the pharmacological effect of anandamide in the mouse model of cannabimimetic activity

    J. Pharmacol. Exp. Ther.

    (1997)
  • M. Cosenza et al.

    Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281

    Synapse

    (2000)
  • W.A. Devane et al.

    Determination and characterization of a cannabinoid receptor in rat brain

    Mol. Pharmacol.

    (1988)
  • W.A. Devane et al.

    Isolation and structure of a brain constituent that binds to the cannabinoid receptor

    Science

    (1992)
  • D.J. Drake et al.

    Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized c-6beta methyl, ethyl, and propyl analogues

    J. Med. Chem.

    (1998)
  • W.S. Edgemond et al.

    Synthesis and characterization of diazomethylarachidonyl ketone: an irreversible inhibitor of n-arachidonylethanolamine amidohydrolase

    J. Pharmacol. Exp. Ther.

    (1998)
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