Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol‐dimethylheptyl at the type 1 and type 2 cannabinoid receptors

Tham, Mylyne; Yılmaz, Orhan; Alaverdashvili, Mariam; Kelly, Melanie E. M.; Denovan‐Wright, Eileen M.; Laprairie, Robert B.

doi:10.1111/bph.14440

Cited by 247 publications

(194 citation statements)

References 59 publications

(112 reference statements)

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“…CBD has a low affinity for the CB1 receptor and functions as a noncompetitive allosteric antagonist. 23,38,39 When used at up to 5 lM, CBD fully inhibited the 2-LG re-sponse and substantially inhibited (*70%) the ACEA and AEA responses. However, its effect on 2-AG at this concentration was less pronounced, but others have also showed that it does not fully inhibit maximal 2-AG responses at this concentration in a similar b-arrestin recruitment assay.…”

Section: Discussionmentioning

confidence: 99%

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

Williams

Doherty

2019

Cannabis and Cannabinoid Research

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Introduction: The cannabinoid type 1 (CB1) receptor and cannabinoid type 2 (CB2) receptor are widely expressed in the body and anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are their best characterized endogenous ligands. The diacylglycerol lipases (diacylglycerol lipase alpha and diacylglycerol lipase beta) not only synthesize essentially all the 2-AG in the body but also generate other monoacylglycerols, including 2linoleoylglycerol (2-LG). This lipid has been proposed to modulate endocannabinoid (eCB) signaling by protecting 2-AG from hydrolysis. However, more recently, 2-LG has been reported to be a CB1 antagonist. Methods: The effect of 2-LG on the human CB1 receptor activity was evaluated in vitro using a cell-based reporter assay that couples CB1 receptor activation to the expression of the b-lactamase enzyme. Receptor activity can then be measured by a b-lactamase enzymatic assay. Results: When benchmarked against 2-AG, AEA, and arachidonoyl-2¢-chloroethylamide (a synthetic CB1 agonist), 2-LG functions as a partial agonist at the CB1 receptor. The 2-LG response was potentiated by JZL195, a drug that inhibits the hydrolysis of monoacylglycerols. The 2-LG response was also fully inhibited by the synthetic CB1 antagonist AM251 and by the natural plant derived antagonist cannabidiol. 2-LG did not potentiate, and only blunted, the activity of 2-AG and AEA. Conclusions: These results support the hypothesis that 2-LG is a partial agonist at the human CB1 receptor and capable of modulating the activity of the established eCBs.

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Section: Discussionmentioning

confidence: 99%

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

Williams

Doherty

2019

Cannabis and Cannabinoid Research

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“…Similarly, (−)-7-hydroxy-dimethylheptyl-CBD can inhibit both AEA uptake and degradation through fatty acid amide hydrolase (FAAH) activity [121]. Recently, (−)-dimethylheptyl-CBD has been shown to be a CB1 receptor agonist ( Table 2) in HEK-293A cells [122]. In addition, by reducing the expression of pro-inflammatory genes (IL-1b, IL-6, and TNF-α), it exhibits a dose-dependent anti-inflammatory effect on microglia BV-2 cells [30].…”

Section: Cb1/cb2 Receptorsmentioning

confidence: 99%

“…Table 2. Influence of natural and synthetic CBD derivatives on receptor activation (X: agonist activation or Y: antagonist activation by related CBD derivative; * weak affinity; #: full name is in chapter 4.1) [2,24,72,76,[114][115][116]120,[122][123][124][125][126][127]130]. Natural CB1 CB2 Gpr55 Gpr18 TRPV1 TRPA1 TRPM8 5-HT…”

Section: Trpv1 5-ht 1a and Adenosine A 2a Receptorsmentioning

confidence: 99%

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

2019

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Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.Antioxidants 2020, 9, 21 2 of 20 Moreover, this phytocannabinoid accelerated wound healing in a diabetic rat model by protecting the endothelial growth factor (VEGF) [11]. In addition, by preventing the formation of oxidative stress in the retina neurons of diabetic animals, CBD counteracted tyrosine nitration, which can lead to glutamate accumulation and neuronal cell death [12].This review summarizes the chemical and biological effects of CBD and its natural and synthetic derivatives. Particular attention was paid to the antioxidant and anti-inflammatory effects of CBD and its derivatives, bearing in mind the possibilities of using this phytocannabinoid to protect against oxidative stress and the consequences associated with oxidative modifications of proteins and lipids. Although CBD demonstrates safety and a good side effect profile in many clinical trials [4], all of the therapeutic options for CBD discussed in this review are limited in a concentration-dependent manner. Molecular Structure of CBDCBD is a terpenophenol compound containing twenty-one carbon atoms, with the formula C 21 H 30 O 2 and a molecular weight of 314.464 g/mol (Figure 1). The chemical structure of cannabidiol, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1, 3-benzenediol, was determined in 1963 [13]. The current IUPAC preferred terminology is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. Naturally occurring CBD has a (−)-CBD structure [14]. The CBD molecule contains a cyclohexene ring (A), a phenolic ring (B) and a pentyl side chain. In addition, the terpenic ring (A) and the aromatic ring (B) are located in planes that are almost perpendicular to each other [15]. There are four known CBD side chain homologs, which are methyl, n-propyl, n-butyl, and n-pentyl [16]. All known CBD forms (Table 1) have absolute trans configuration in positions 1R and 6R [16].

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“…In this sense, it is possible that the diverse effects of CBD over CB1-expressing, heterogeneous neuronal populations may lead to both undesirable and protective consequences. CBD can have opposed effects on CB1 receptors, given that it can act as an indirect agonist (De Petrocellis et al, 2011) and as a biased negative allosteric modulator (Tham et al, 2019). The complex pharmacology of this phytocannabinoid possess interesting properties for the management of different neuropsychiatric conditions but can also lead to some undesirable effects that are especially hard to predict (Brown and Winterstein, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Its main molecular effects within the central nervous system are comprehended by the agonism of 5-HT1A, TRPV1, G-protein receptor 55 (GPR55), peroxisome proliferator-activated gamma (PPARγ) receptors and the antagonism of adenosine reuptake (Turner et al, 2017). Despite initial controversy about its endocannabinoid targets (Zlebnik and Cheer, 2016), recent evidence also supports CBD as a negative 6 allosteric modulator of CB1 and CB2 receptors at physiologically relevant concentrations (Laprairie et al, 2015;Martínez-Pinilla et al, 2017;McPartland et al, 2015;Navarro et al, 2018;Tham et al, 2019). In addition, CBD reduces anandamide (AEA) metabolism by inhibiting fatty acid amid hydrolase (FAAH) enzymatic activity (De Petrocellis et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

Luján

Alegre-Zurano

Martín‐Sánchez

et al. 2020

Preprint

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Cocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8-12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates 'extinction burst' responding after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism.Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a 3 crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.

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Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol‐dimethylheptyl at the type 1 and type 2 cannabinoid receptors

Abstract: The pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB and CB receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB and CB receptors.

Cited by 247 publications

References 59 publications

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

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