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New Approaches and Challenges to Targeting the Endocannabinoid

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New Approaches and Challenges to Targeting the Endocannabinoid PERSPECTIVES G protein‑coupled receptors (GPCRs) — OPINION cannabinoid receptor 1 (CB1) and CB2 (REFS7,8) — and that CB1 is responsible New approaches and challenges for the psychoactive effects of marijuana5,6,9. However, to date, no specific receptor for CBD has been identified. Several different to targeting the endocannabinoid molecular targets have been suggested to mediate distinct pharmacological effects of system this cannabinoid. The identification of CB1 and CB2 led Vincenzo Di Marzo to the isolation and characterization of endogenous ligands for these proteins, Abstract | The endocannabinoid signalling system was discovered because N‑arachidonoyl‑ethanolamine (AEA) receptors in this system are the targets of compounds present in psychotropic and 2‑arachidonoylglycerol (2‑AG)10–12 preparations of Cannabis sativa. The search for new therapeutics that target (FIG. 1), which were named the endo‑ endocannabinoid signalling is both challenging and potentially rewarding, as cannabinoids13, and of five main enzymes endocannabinoids are implicated in numerous physiological and pathological for their biosynthesis and inactivation: N‑acyl‑phosphatidylethanolamine‑ processes. Hundreds of mediators chemically related to the endocannabinoids, hydrolysing phospholipase D (NAPE‑PLD), often with similar metabolic pathways but different targets, have complicated the sn‑1‑specific diacylglycerol lipase‑α (DGLα), development of inhibitors of endocannabinoid metabolic enzymes but have also DGLβ, fatty acid amide hydrolase 1 (FAAH) stimulated the rational design of multi-target drugs. Meanwhile, drugs based on and monoacylglycerol lipase (MAGL; also 14–17 botanical cannabinoids have come to the clinical forefront, synthetic agonists known as MGL) . This system of two designed to bind cannabinoid receptor 1 with very high affinity have become a signalling lipids, their two receptors and their metabolic enzymes became known as societal threat and the gut microbiome has been found to signal in part through the endocannabinoid system and was soon the endocannabinoid network. The current development of drugs that alter assigned a wealth of physiological roles that endocannabinoid signalling and how this complex system could be went far beyond what could be predicted pharmacologically manipulated in the future are described in this Opinion article. from the pharmacological actions of THC18. Later, alterations in endocannabinoid signalling, owing to changes in the expression and function of cannabinoid receptors and Along with its controversial recreational Despite the fact that CBD and THC were endocannabinoid metabolic enzymes, as use, the recent history of psychotropic identified at almost the same time, most of well as modified endocannabinoid tissue preparations of Cannabis sativa has the pharmacological efforts were dedicated concentrations, were found to be associated been marked by their ever increasing, to understanding the mechanism of action with diverse pathological conditions. although mostly anecdotal, therapeutic of THC, and, initially, relatively few studies Therapies that exploit or correct such applications for a wide variety of ailments1. investigated the effects of CBD. This was alterations might therefore be developed When, in the mid‑1950s and 1960s2–4, the possibly for two reasons: the need to fully from agonists or antagonists of CB1 or CB2 first chemical constituents of cannabis appreciate the potential toxicological and or from inhibitors of endocannabinoid were identified, it was imagined that the addictive effects of the principal psychoactive degradation or biosynthesis19. medicinal activity of this plant could be component of what had become (and still is) The road to the clinical development of teased out from its psychotropic effects. the most widely used illicit drug in Western synthetic endocannabinoid system‑based The first cannabinoids to be chemically societies; and the fact that the varieties of drugs (TABLE 1) has been paved with characterized, cannabidiol (CBD)3 and cannabis used recreationally, in which THC great hopes and bitter disappointments. Δ9‑tetrahydrocannabinol (THC)4, were the was most abundant, were perceived as the In the meantime, plant cannabinoids, most abundant members of this class of ones with the most promising therapeutic particularly CBD, either alone or in natural products in the dried and heated effects. However, there was really no reason combination with THC, have come back flowers of C. sativa varieties that are used to believe that such effects were exclusively into the limelight as efficacious and for the production of hemp and marijuana, caused by THC nor that preparations from moderately safe therapeutic drugs20,21. respectively. Accordingly, CBD was found non‑psychotropic varieties of cannabis, Several endocannabinoid‑ based drugs and to be non‑psychotropic, whereas THC is in which CBD was often most abundant, their therapeutic applications have been responsible for the psychoactive effects of would not have therapeutic value. We thoroughly reviewed in this journal19. Here, marijuana5,6. now understand that THC acts via two I provide some explanation of what has gone NATURE REVIEWS | DRUG DISCOVERY ADVANCE ONLINE PUBLICATION | 1 ©2018 Spri nger Nature Li mited. All ri ghts reserved. PERSPECTIVES wrong so far with these molecules and Targeting cannabinoid receptors anecdotal data had previously suggested why. I also discuss various possible ways CB1 and CB2. CB1 is possibly the most that marijuana is effective. Subsequent out of this impasse and highlight the role abundant and widespread GPCR in the preclinical studies confirmed that the of the gut microbiota as a potential source mammalian brain. This has made the activation of CB1 in peripheral and central of information for new endocannabinoid-­ therapeutic use of THC very difficult nervous system (CNS) cells (including based therapies. in pathological conditions for which but not exclusively neurons) might be beneficial in neuropathic and inflammatory OA and other primary fatty acid amides pain; neuropsychiatric disorders including anxiety, depression and post‑traumatic stress disorder; neurological diseases NAEs Non specific targets (including CB1) 2-AcGs such as multiple sclerosis and Huntington disease chorea; and inflammatory bowel PPAR γ disorders22–25. By contrast, the use of CB1 PPARα antagonists or inverse agonists for conditions in which CB1 overactivation may contribute DHEA to the progression or symptoms of a disease — such as obesity, type 2 diabetes, GPR110 hepatic or kidney disorders and even some neurological conditions such as Alzheimer PEA disease and schizophrenia24,26,27 — has been GPR55 proposed. However, the endocannabinoid system is often activated on demand and in a cell‑specific and time‑specific manner during pathological states to exert a homeostatic GPR119 function19. Hence, the use of systemic direct or inverse agonists, which indiscriminately activate or inhibit the function of all CB1 molecules, can interfere with normal CB1 CB2 function in non‑target cells. Typical examples of unwanted effects of such compounds are OEA LEA AEA 2-AG 2-OG 2-LG the intoxication associated with CB1 agonists (which might also interfere with cognitive CB1 functions)28 and the anxiety and depression caused by CB1 antagonists or inverse agonists29. Thus, rimonabant (Acomplia), a CB1 inverse agonist marketed in Europe TRPV1 N-acyl- N-acyl- serotonins dopamines in 2006 for the treatment of obesity and the metabolic syndrome, had to be withdrawn in 2008 because it induced depression and Ca 3 N-acyl- N-acyl- v suicidal ideation in a subset of patients29. taurines glycines For CB1 activators, marinol (botanical THC) and nabilone (a synthetic THC GPR18 analogue) are employed for the treatment of cachexia in cancer and AIDS and for chemotherapy‑ induced nausea, but their very narrow therapeutic window prevents their TRPV4 widespread use30 (TABLE 1). N-acyl- Peripherally restricted agonists and ? serines antagonists for CB1 (compounds with very Lipoamino acids Acyl neurotransmitters low penetration through the blood–brain barrier) were next designed and found to be Figure 1 | Endocannabinoidome mediators and receptors. The main endocannabinoids, devoid of CNS side effects31. Efforts have also N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoylglycerol (2Nature-AG), are Reviews part of |larger Drug familiesDiscovery of been dedicated to develop indirect agonists: lipids, the N-acylethanolamines (NAEs) and the 2-acylglycerols (2-AcGs), respectively. Numerous other drugs that act on only the populations members of these families signal through other G protein-coupled receptors (GPCRs), ion channels of receptors that are subject to defective and nuclear receptors, as shown. In addition, long-chain primary fatty acid amides, lipoamino acids and acyl neurotransmitters signal through some of the receptors used by NAEs and 2-AcGs. 2-LG, activation by endocannabinoids. These 2+ indirect agonists inhibit the inactivation of 2-linoleoyl glycerol; 2-OG, 2-oleoyl glycerol; Cav3, T-type Ca channel; CB, cannabinoid receptor; DHEA, N‑docosahexaenoyl ethanolamine; GPR18, G protein-coupled receptor 18; LEA, N‑linoleoyl endocannabinoids by catabolic enzymes ethanolamine; OA, oleamide; OEA, N-oleoylethanolamine; PEA, N-palmitoylethanolamine; PPAR, (see section below on endocannabinoid peroxisome proliferator-activated receptor; TRPV1, transient receptor potential cation channel sub- metabolism)32–36 or enhance their activity family
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