Inhibition of Anandamide Amidase Activity in Mouse Brain Microsomes by Cannabinoids.

Watanabe, Kazuhito; Kayano, Yuichiro; Matsunaga, Tamihide; Yamamoto, Ikuo; Yoshimura, Hidetoshi

doi:10.1248/bpb.19.1109

Cited by 106 publications

(75 citation statements)

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“…with an IC 50 420 mM). The activity of CBD in this study was higher than that previously reported for anandamide hydrolysis by mouse brain (Watanabe et al, 1996;, where however only a very high concentration of the compound (160 mM) was used.…”

Section: Effect Of Cbd Analogues On Fatty Acid Amide Hydrolasecontrasting

confidence: 78%

“…As it was found to inhibit the reuptake and hydrolysis of AEA in vitro (Rakhshan et al, 2000;Watanabe et al, 1996), it is possible that CBD acts in part by interfering with AEA inactivation, thereby enhancing the putative tonic inhibitory action of AEA on in¯ammation. The fact that the pharmacological actions of CBD are not in¯uenced by CB 1 /CB 2 receptor antagonists should not be taken as evidence against this hypothesis, since it is now established that AEA also acts upon non-cannabinoid receptor targets, including VR1 receptors and TASK-1 K + channels (Zygmunt et al, 1999;Maingret et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…These proteins are: (i) fatty acid amide hydrolase (FAAH) (Cravatt et al, 1996), the intracellular enzyme catalysing the hydrolysis of the endogenous cannabinoid ligand, anandamide (arachidonoylethanolamide, AEA) (Ueda et al, 2000, for review); and (ii) the`anandamide membrane transporter' (AMT) (Di Marzo et al, 1994), which facilitates the transport of AEA across the cell membrane and, subsequently, its intracellular degradation (Hillard & Jarrahian, 2000, for review). It was found that CBD inhibits both AEA hydrolysis by FAAH-containing membrane preparations (Watanabe et al, 1996), and AEA uptake by RBL ± 2H3 cells via the AMT (Rakhshan et al, 2000). Although these e ects were observed at high mM concentrations, these ®ndings raised the possibility that some of the pharmacological actions of CBD might be due to inhibition of AEA degradation, with subsequent enhancement of the endogenous levels of this mediator, for which neuroprotective (Hansen et al, 1998) and antiin¯ammatory (Di Marzo et al, 2000a) properties have been previously suggested.…”

Section: Introductionmentioning

confidence: 99%

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Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Bisogno¹,

Hanŭs

Petrocellis

et al. 2001

British J Pharmacology

1,165

817

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1 (7)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-in¯ammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). 2 CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca 2+ concentrations in cells over-expressing human VR1; (b) [ 14 C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [ 14 C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. 3 Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC 50 =3.2 ± 3.5 mM, and with a maximal e ect similar in e cacy to that of capsaicin, i.e. 67 ± 70% of the e ect obtained with ionomycin (4 mM). CBD (10 mM) desensitized VR1 to the action of capsaicin. The e ects of maximal doses of the two compounds were not additive. 4 (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [ 14 C]-AEA uptake (IC 50 =10.0 and 7.0 mM); the (7)-enantiomers were slightly less active (IC 50 =14.0 and 12.5 mM). CBD and (+)-CBD were also active (IC 50 =22.0 and 17.0 mM). 5 CBD (IC 50 =27.5 mM), (+)-CBD (IC 50 =63.5 mM) and (7)-7-hydroxy-CBD (IC 50 =34 mM), but not the other analogues (IC 50 4100 mM), weakly inhibited [ 14 C]-AEA hydrolysis. 6 Only the (+)-isomers exhibited high a nity for CB 1 and/or CB 2 cannabinoid receptors. 7 These ®ndings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological e ects of CBD and its analogues. In view of the facile high yield synthesis, and the weak a nity for CB 1 and CB 2 receptors, (7)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.

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Section: Effect Of Cbd Analogues On Fatty Acid Amide Hydrolasecontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Bisogno¹,

Hanŭs

Petrocellis

et al. 2001

British J Pharmacology

1,165

817

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show abstract

“…CBD has been implicated in modulating the metabolism of the endocannabinoid, arachidonoylethanolamide (AEA; also 'anandamide') in vitro [118,119]. Transporter proteins are involved in regulating AEA-mediated cellular signaling and have also been reported to be targets for CBD [19,71].…”

Section: Anandamide Transportersmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…CBD has minimal affinity for CB1 receptors (Pertwee, 1997b), although it appears to interact with the endocannabinoid system via fatty acid amide hydrolase (Watanabe et al, 1996) or through the putative anandamide membrane transporter (Bisogno et al, 2001). CBD also has been found to have agonist activity at TRPV1 (Bisogno et al, 2001) and at 5-HT1A receptors (Russo et al, 2005).…”

Section: Putative Mechanisms For Thc and Cbd Interactionsmentioning

confidence: 99%

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

Vann

Gamage

Warner

et al. 2008

Drug and Alcohol Dependence

114

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Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Δ 9 -tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC's effects by these other cannabinoids [e.g., cannabidiol (CBD)] has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC's abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/ A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10 mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC's discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios.

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Inhibition of Anandamide Amidase Activity in Mouse Brain Microsomes by Cannabinoids.

Cited by 106 publications

References 0 publications

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Molecular Targets of Cannabidiol in Neurological Disorders

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

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