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The Endocannabinoid System As a Target for Therapeutic Drugs Daniele Piomelli, Andrea Giuffrida, Antonio Calignano and Fernando Rodríguez De Fonseca

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The Endocannabinoid System As a Target for Therapeutic Drugs Daniele Piomelli, Andrea Giuffrida, Antonio Calignano and Fernando Rodríguez De Fonseca REVIEW The endocannabinoid system as a target for therapeutic drugs Daniele Piomelli, Andrea Giuffrida, Antonio Calignano and Fernando Rodríguez de Fonseca Cannabinoid receptors, the molecular targets of the cannabis constituent D9-tetrahydrocannabinol, are present throughout the body and are normally bound by a family of endogenous lipids – the endocannabinoids. Release of endocannabinoids is stimulated in a receptor-dependent manner by neurotransmitters and requires the enzymatic cleavage of phospholipid precursors present in the membranes of neurons and other cells. Once released, the endocannabinoids activate cannabinoid receptors on nearby cells and are rapidly inactivated by transport and subsequent enzymatic hydrolysis. These compounds might act near their site of synthesis to serve a variety of regulatory functions, some of which are now beginning to be understood. Recent advances in the biochemistry and pharmacology of the endocannabinoid system in relation to the opportunities that this system offers for the development of novel therapeutic agents will be discussed. Since the discovery of the first cannabinoid receptor 12 years damide can be catalytically hydrolysed by an amidohydrolase10, ago1,2, important advances have been made in several areas of whose gene has been cloned11 (Fig. 1). cannabinoid pharmacology. Endocannabinoid compounds The most likely route of 2-AG biosynthesis involves the and their pathways of biosynthesis and inactivation have been same enzymatic cascade that catalyses the formation of the identified, and the molecular structures and anatomical dis- second messengers inositol (1,4,5)-trisphosphate and 1,2- tribution of cannabinoid receptors have been investigated diacylglycerol (DAG) (Fig. 2). Phospholipase C (PLC), acting in detail. Pharmacological agents that interfere with various on phosphatidylinositol (4,5)-bisphosphate, generates DAG, aspects of the endocannabinoid system have been developed, which is converted to 2-AG by DAG lipase12. 2-AG might and pathophysiological circumstances in which this system also be synthesized by the hydrolysis of lysophospholipids or might be active have begun to emerge. The manner in triacylglycerols6. Regardless of the mechanism involved, D. Piomelli, which these discoveries might impact our understanding of 2-AG formation can be triggered by neural activity12 or by Professor of endocannabinoid signaling and help unlock its potential for occupation of membrane receptors13. Following its release, Pharmacology, University of developing novel therapeutic agents will be discussed. 2-AG can be taken up by cells via the anandamide transport California, Irvine, system9 and hydrolysed by an unknown monoacylglycerol 92697-4625, USA. Endogenous cannabinoids lipase activity14 (Fig. 2). E-mail: piomelli@ uci.edu The two endocannabinoids isolated so far – anandamide and Thus, anandamide and 2-AG can be released from neuronal A. Giuffrida, 2-arachidonylglycerol (2-AG)3–5 – are lipid in nature but and non-neuronal cells when the need arises, utilizing analo- Researcher, differ from amino acid, amine and peptide transmitters in gous but distinct receptor-dependent pathways. The non- Department of Pharmacology, ways other than just their chemical structures. Classical and synaptic release mechanisms and short life spans of anan- E-mail: agiuffri@ peptide transmitters are synthesized in the cytosol of neurons damide and 2-AG suggest that these compounds might act uci.edu and stored in synaptic vesicles, from where they are secreted near their site of synthesis to regulate the effects of primary A. Calignano, Associate Professor, by exocytosis following excitation of nerve terminals by action messengers, such as neurotransmitters and hormones. Department of potentials. By contrast, anandamide and 2-AG can be pro- Experimental duced upon demand by receptor-stimulated cleavage of mem- Inhibitors of anandamide inactivation Pharmacology, University of Naples, brane lipid precursors and released from cells immediately Drugs that block the formation or inactivation of anandamide ‘Federico II’, Via after their production. and 2-AG should help identify the physiological functions Domenico Montesano, Anandamide can be produced from the hydrolysis of of these compounds and might be beneficial in disease states 49, Naples, 80131, Italy. an N-acylated species of phosphatidylethanolamine (PE) in which regulation of endocannabinoid levels might produce E-mail: caligna@ N-arachidonyl PE, a process catalysed by phospholipase D more selective responses than those elicited by cannabinoid unina.it (PLD)6 (Fig. 1). The stimulation of neurotransmitter receptors receptor ligands. Although this area of pharmacology is still and F. Rodríguez de appears to play a determinant role in initiating this reaction, largely unexplored, inhibitors of the two main steps of anan- Fonseca, as indicated by the finding that anandamide release in the damide disposition (membrane transport and intracellular Associate Professor, striatum is strongly enhanced by activation of dopamine D2 hydrolysis) have recently become available. Department of 7 Psychobiology, receptors . Once released, anandamide can act on cannabinoid Anandamide transport is inhibited by the compound Complutense receptors or accumulate back into cells via an energy- and AM404 (Figs 1,3). This drug potentiates various responses University, Madrid, Na1-independent transport system8. The selectivity of this elicited by exogenous anandamide and interacts very poorly 28233, Spain. 9 8,15 E-mail: frdefonseca@ system for anandamide has been documented but its mol- with cannabinoid CB1 receptors . For example, AM404 en- psi.ucm.es ecular structure remains uncharacterized. Inside cells, anan- hances anandamide-induced hypotension without producing 218 TiPS – June 2000 (Vol. 21) 0165-6147/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01482-6 REVIEW direct vasodilatory effects16. Furthermore, when applied alone, N-arachidonyl PE PE AM404 decreases motor activity15,17 and elevates the levels H OH OH N H N O P O 2 O P O of circulating anandamide (A. Giuffrida et al., unpublished). O However, AM404 can accumulate in cells where it might O 2 O reach concentrations that are sufficient to inhibit anandamide OO OO amidohydrolase9 (M. Beltramo and D. Piomelli, unpublished). R R R R NAT Anandamide amidohydrolase is blocked reversibly by transition state analogs such as arachidonyltrifluoromethyl- PLD O 1 OOR ketone (ATFMK), which might act by forming a stable inter- O 18 mediate with a serine residue at the enzyme active site O P O O N(CH3)2 (Fig. 3). Moreover, irreversible inhibition can be achieved OH OH N with a variety of compounds including the fatty acid sulfonyl H PC fluoride AM374 (Ref. 18) (Figs 1,3). AM374, one of the Anandamide most potent anandamide amidohydrolase inhibitors identified AM404 thus far, potentiates anandamide responses in vitro and in vivo, 3 4 but its specificity is limited by a relatively high affinity for Extracellular 19 CB1 receptors . Cannabinoid receptors CB AT The two cannabinoid receptor subtypes characterized so far, CB and CB , belong to the superfamily of G-protein-coupled 1 2 γ α membrane receptors (GPCRs)2,20. Their molecular and phar- AAH β Intracellular macological properties have recently been reviewed21. Three 5 Gi issues that might be relevant to the use of cannabinoid agents O Anandamide in medicine will be discussed: (1) the apparently exclusive OH role of CB1 receptors in mediating central cannabinoid effects; (2) the rapid tolerance that results from repeated cannabinoid AM374 Arachidonic acid administration; and (3) the possible existence of multiple cannabinoid receptors in peripheral tissues. NH HO 2 Although CB receptors are expressed throughout the body, Biological 1 responses Ethanolamine they are particularly abundant in the CNS where, despite a great deal of effort, no other cannabinoid receptor subtype has trends in Pharmacological Sciences yet been found. This unusual situation – most neurotrans- Fig. 1. Formation and inactivation of anandamide. Anandamide can be generated by hydrolysis of mitters act on multiple CNS receptors – accords with data N-arachidonyl phosphatidylethanolamine (N-arachidonyl PE), which is catalysed by phospholipase D that indicate that a single pharmacological site accounts for all (PLD) (1)6. The synthesis of N-arachidonyl PE, depleted during anandamide formation, might be medi- ated by N-acyl transferase activity (NAT) (2), which detaches an arachidonate moiety (red) from the central effects of cannabimimetic drugs, whether therapeuti- sn-1 position of phospholipids such as phosphatidylcholine (PC) and transfers it to the primary amino cally favorable (e.g. analgesia) or harmful (e.g. dysphoria and group of PE. The membrane localizations of PLD and NAT are speculative. Newly formed anandamide amnesia). Consequently, although potent CB receptor ag- can be released into the extracellular space, where it can activate G-protein-coupled cannabinoid (CB) 1 receptors located on neighboring cells (3) or on the same cells that produce anandamide (not shown). onists have been available for some time (Table 1), the thera- Anandamide release in the external milieu has been demonstrated both in vitro and in vivo 6,7. Anandamide peutic development of these compounds has been very limited. can be removed from its sites of action by carrier-mediated transport (anandamide transport, AT) (4)8,9, Given this situation, how might centrally active
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