The Endocannabinoid System: Current Pharmacological Research and Therapeutic Possibilities

Jonsson, Kent-Olov; Holt, Sandra; Fowler, Christopher J.

doi:10.1111/j.1742-7843.2006.pto_376.x

Cited by 47 publications

(30 citation statements)

References 136 publications

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“…Inhibitors of AEA and 2-AG degradation offer a potentially attractive alternative strategy to stimulate the endocannabinoid system (9)(10)(11)(12). Indeed, despite the structural similarity shared by AEA and 2-AG, distinct enzymes inactivate these lipids and thus serve as key points of control over specific endocannabinoid signaling events in vivo (13).…”

mentioning

confidence: 99%

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Long

Nomura

Vann

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

348

420

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⌬ 9 -Tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes.hydrolase ͉ inhibitor ͉ metabolism N -arachidonoyl ethanolamine (anandamide or AEA) (1) and 2-arachidonoylglycerol (2-AG) (2, 3) are lipid transmitters that serve as endogenous ligands for the cannabinoid G-proteincoupled receptors CB1 and CB2. These lipids and receptors, along with the enzymes that biosynthesize and degrade AEA and 2-AG, form the endogenous cannabinoid (endocannabinoid) system, which regulates a diverse number of physiological processes in mammals, including pain, cognition, emotionality, neurodegeneration, feeding, and inflammation (4).CB1 and CB2 receptors are also activated by ⌬ 9 -tetrahydrocannabinol (THC), the psychoactive component of marijuana (4). Most of the neurobehavioral effects of THC and other direct cannabinoid receptor agonists are mediated by the CB1 receptor (5, 6), likely reflecting its widespread and abundant expression in the nervous system (7,8). CB1 agonism produces medicinally useful activities, such as analgesia, but also a number of undesirable side effects, including locomotor and cognitive impairments, as well as abuse liability. To date, it has proved difficult to uncouple these beneficial and untoward properties, thus limiting the therapeutic utility of direct CB1 agonists.Inhibitors of AEA and 2-AG degradation offer a potentially attractive alternative strategy to stimulate the endocannabinoid system (9-12). Indeed, d...

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mentioning

confidence: 99%

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Long

Nomura

Vann

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

348

420

View full text Add to dashboard Cite

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“…However, the cloning of two G-protein-coupled receptors, CB 1 and CB 2 (Matsuda et al, 1990;Munro et al, 1993), that specifically bind cannabinoids, precipitated the discovery of the endocannabinoid system, consisting of cannabinoid receptors, endogenous endocannabinoids and the enzymes required for their synthesis and degradation (Piomelli, 2003;Jonsson et al, 2006). CB 1 cannabinoid receptors (CB 1 ) are present in ocular tissues of both the inflow and outflow pathways, including the TM (Straiker et al, 1999;Porcella et al, 2000;Stamer et al, 2001).…”

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confidence: 99%

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

McIntosh

Hudson

Yegorova

et al. 2007

British J Pharmacology

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Background and purpose: Trabecular meshwork (TM) is an ocular tissue involved in the regulation of aqueous humour outflow and intraocular pressure (IOP). CB 1 receptors (CB 1 ) are present in TM and cannabinoid administration decreases IOP. CB 1 signalling was investigated in a cell line derived from human TM (hTM). Experimental approach: CB 1 signalling was investigated using ratiometric Ca 2 þ imaging, western blotting and infrared In-Cell Western analysis. Key results: WIN55212-2, a synthetic aminoalkylindole cannabinoid receptor agonist (10-100 mM) increased intracellular Ca 2 þ in hTM cells. WIN55,212-2-mediated Ca 2 þ increases were blocked by AM251, a CB 1 antagonist, but were unaffected by the CB 2 antagonist, AM630. The WIN55,212-2-mediated increase in [Ca 2 þ ] i was pertussis toxin (PTX)-insensitive, therefore, independent of G i/o coupling, but was attenuated by a dominant negative Ga q/11 subunit, implicating a G q/11 signalling pathway. The increase in [Ca 2 þ ] i was dependent upon PLC activation and mobilization of intracellular Ca 2 þ stores. A PTXsensitive increase in extracellular signal-regulated kinase (ERK1/2) phosphorylation was also observed in response to WIN55,212-2, indicative of a G i/o signalling pathway. CB 1 -G q/11 coupling to activate PLC-dependent increases in Ca 2 þ appeared to be specific to WIN55,212-2 and were not observed with other CB 1 agonists, including CP55,940 and methanandamide. CP55940 produced PTX-sensitive increases in [Ca 2 þ ] i at concentrations Z15 mM, and PTX-sensitive increases in ERK1/2 phosphorylation. Conclusions and implications: This study demonstrates that endogenous CB 1 couples to both G q/11 and G i/o in hTM cells in an agonist-dependent manner. Cannabinoid activation of multiple CB 1 signalling pathways in TM tissue could lead to differential changes in aqueous humour outflow and IOP.

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“…Many excellent recent reviews have considered the therapeutic utilities of cannabinoid agonists, antagonists and inverse agonists [Cervino et al, 2007;Jonsson et al, 2006;Makriyannis et al, 2005;Pertwee, 2005b;Ramos et al, 2005]. The major therapeutic use for cannabinoid inverse agonists/antagonists has centered on the treatment of metabolic syndrome and obesity [Antel et al, 2006;Cervino et al, 2007] [Jagerovic et al, 2008].…”

Section: Therapeutic Uses For Cannabinoid Inverse Agonists/antagonistsmentioning

confidence: 99%

Toward the design of cannabinoid CB₁ receptor inverse agonists and neutral antagonists

Reggio

2009

Drug Development Research

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The cannabinoid CB 1 receptor belongs to Class A of the G-protein-coupled receptor (GPCR) family. The high constitutive activity of CB 1 facilitates inverse agonism at this receptor, and CB 1 inverse agonists/antagonists have recently been considered for the treatment of obesity and metabolic syndrome. GPCRs are assumed to have a common topology and to share a common molecular activation mechanism involving their intracellular domains. However, each individual receptor will also have a molecular switch within the ligand binding pocket that is a noncovalent intramolecular interaction in the basal state of the GPCR that must be disrupted to achieve an active state or stabilized to maintain the inactive state. Knowledge of the molecular switch within the ligand binding pocket can greatly facilitate the rational design of inverse agonists and neutral antagonists. This review begins with a brief review on the CB 1 receptor and its ligands. The review then focuses on the experimental literature on GPCR structure and activation in Class A receptors. The identification of the molecular switch region in the ligand binding pocket of CB 1 (F3.36/W6.48) is discussed and the combined mutation and modeling studies that have led to the identification of interactions key to the inverse agonism of SR141716A are presented. Finally, the development of the first CB 1 neutral antagonists based on these modeling/mutation results is discussed. Drug Dev Res 70 : 585-600, 2009.

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The Endocannabinoid System: Current Pharmacological Research and Therapeutic Possibilities

Cited by 47 publications

References 136 publications

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Toward the design of cannabinoid CB₁ receptor inverse agonists and neutral antagonists

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The Endocannabinoid System: Current Pharmacological Research and Therapeutic Possibilities

Cited by 47 publications

References 136 publications

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Toward the design of cannabinoid CB1 receptor inverse agonists and neutral antagonists

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Toward the design of cannabinoid CB₁ receptor inverse agonists and neutral antagonists