Highly Selective CB1 Cannabinoid Receptor Ligands and Novel CB1/VR1 Vanilloid Receptor “Hybrid” Ligands

Marzo, Vincenzo Di; Bisogno, Tiziana; Petrocellis, Luciano De; Brandi, Ines; Jefferson, Renée G.; Winckler, Ramona; Davis, John B.; Dasse, O. A.; Mahadevan, Anu; Razdan, Raj K.; Martin, Billy R.

doi:10.1006/bbrc.2001.4354

Cited by 113 publications

(88 citation statements)

References 24 publications

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“…Similarly, SR144528 elicited a partial attenuation of the FAAH (-/-) anti-edema phenotype in one study , but not in another study . AEA also has been reported to produce anti-inflammatory effects via its actions at TRPV1 receptors (De Petrocellis et al, 2001;Di Marzo et al, 2001a).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

et al. 2008

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While it has long been recognized that Δ 9 -tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal antiedema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay.

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Section: Discussionmentioning

confidence: 99%

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

et al. 2008

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“…1) were used to assess the effects of CB1 receptor deletion on cannabinoid disruption of lever press responding. Whereas ⌬ 9 -THC binds with similar affinity to cannabinoid CB1 receptors (K i ϭ 40.7 Ϯ 1.7 nM) and CB2 receptors (K i ϭ 36.4 Ϯ 10 nM) (Showalter et al, 1996), methanandamide and O-1812 bind with considerably higher affinity to CB1 receptors (K i ϭ 137 Ϯ 20 and K i ϭ 3.4 Ϯ 0.5 nM, respectively) (Adams et al, 1995;Di Marzo et al, 2001a) than to CB2 receptors (K i ϭ 3024 Ϯ 705 and K i ϭ 3870 Ϯ 235 nM, respectively) (our unpublished data; Di Marzo et al, 2001a). To evaluate the pharmacological specificity of effects in this model, we also tested three drugs (morphine, ethanol, and diazepam) that share pharmacological effects with cannabinoids in other assays, albeit these effects are mediated via different (noncannabinoid) mechanisms (Wiley and Martin, 2003).…”

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Differential Effects of Δ⁹-Tetrahydrocannabinol and Methanandamide in CB1 Knockout and Wild-Type Mice

Baskfield¹,

Martin²,

Wiley

2004

J Pharmacol Exp Ther

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Mice devoid of CB1 cannabinoid receptors (CB1Ϫ/Ϫ mice) provide a unique opportunity to further investigate the role of CB1 receptors in exocannabinoid and endocannabinoid effects. CB1Ϫ/Ϫ mice (N ϭ 18) and their wild-type littermates (CB1ϩ/ϩ mice; N ϭ 12) were placed in standard mouse operant chambers and trained to lever press under a fixed ratio 10 schedule of reinforcement. When stable lever press responding under the fixed ratio 10 schedule had been established, cannabinoids and noncannabinoids were administered to both groups. CB1ϩ/ϩ mice acquired the lever press response more readily than CB1Ϫ/Ϫ mice. ⌬ 9 -Tetrahydrocannabinol (⌬ 9 -THC) decreased lever press responding in CB1ϩ/ϩ mice only, whereas methanandamide, a metabolically stable endocannabinoid analog, produced similar response rate decreases in both genotypic groups. Similar to ⌬ 9 -THC, another endocannabinoid analog, (R)- (20-cyano-16,16-dimethyl docosa-cis-5,8,11,14--THC, but not those of methanandamide. Because methanandamide binds poorly to CB2 receptors, these results suggest possible non-CB1, non-CB2 mechanisms of action for methanandamide-induced behavioral disruption of lever press responding. Ethanol and morphine elicited greater response decreases in CB1Ϫ/Ϫ mice than in CB1ϩ/ϩ mice, suggesting a possible role of CB1 receptors in the rate disruptive effects of these drugs. In contrast, diazepam did not produce between group differences, suggesting that CB1 receptors are not involved in diazepam-induced disruption of lever press responding. ⌬9 -Tetrahydrocannabinol (⌬ 9 -THC), the principle psychoactive constituent of marijuana and other natural, synthetic, and endocannabinoids, elicits a well characterized syndrome of pharmacological effects in laboratory animals (Dewey, 1986;Martin et al., 1991). These effects, including hypothermia, hypoactivity, antinociception, and catalepsy, are attributed mainly to the actions of cannabinoids at CB1 cannabinoid receptors in the brain (Martin et al., 1991). Recently, recombinant DNA techniques have made possible the development of CB1 receptor knockout mice (CB1Ϫ/Ϫ) Zimmer et al., 1999). These mice lack CB1 receptors and provide a unique opportunity to further investigate the role of these receptors in the pharmacological effects of cannabinoids. Research with CB1Ϫ/Ϫ mice demonstrates that the characteristic antinociceptive, hypoactive, and cataleptic effects of ⌬ 9 -THC are absent in these mice Di Marzo et al., 2000). Moreover, ⌬ 9 -THC stimulates [ 35 S]GTP␥S binding in brain membranes of CB1ϩ/ϩ mice, but not in those of CB1Ϫ/Ϫ mice (Di Marzo et al., 2000).Thus far, the measures examining the pharmacological effects of cannabinoids in CB1Ϫ/Ϫ mice, albeit important, represent unlearned responses. Previous research has demonstrated that cannabinoids, including ⌬ 9 -THC, WIN 55,212-2, and methanandamide, also disrupt performance in the Morris water maze, a working memory task (Varvel and Lichtman, 2002). The effects of cannabinoids on schedulecontrolled operant behavior have not been investiga...

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“…More recently, despite the fact that similar structural prerequisites are necessary for long-chain fatty acid derivatives to interact with both the human VR 1 and the AMT, selective VR 1 agonists and AMT competitive inhibitors could be developed (De Petrocellis et al, 2000). CB 1 /VR 1 hybrid agonists were designed as possible analgesic, anti-inflammatory and antitumor agents (Melck et al, 1999;Di Marzo et al, 2000b, 2001b. For one of these hybrids, named arvanil ( Fig.…”

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“…1), the chemical modification of the fatty acid chain, and, particularly, the introduction of two methyl groups on the C-16 and of a bromine group instead of the methyl group on the C-20, led to a compound, O-1861 ( Fig. 1), with nearly the same activity on VR 1 and CB 1 receptors and high potency in the mouse tetrad of behavioral tests of cannabimimetic activity in vivo (Di Marzo et al, 2001b). These tests consist of: 1) inhibition of spontaneous activity in an open field, 2) rectal hypothermia, 3) analgesia in the tail-flick test, and 4) immobility on a ring.…”

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A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

Marzo¹,

Griffin²,

Petrocellis³

et al. 2002

J Pharmacol Exp Ther

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Arvanil, a structural "hybrid" between the endogenous cannabinoid CB 1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR 1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivatives prepared by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB 1 receptors, activate VR 1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB 1 receptor. Methylation of the amide group decreased the activity at VR 1 , AMT, and FAAH. On the aromatic ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR 1 and AMT, but not the affinity for CB 1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR 1 and AMT but exhibited little affinity for CB 1 receptors. The urea analog was a potent FAAH inhibitor (IC 50 ϭ 2.0 M). A water-soluble analog of arvanil, O-2142, was as active on VR 1 , much less active on AMT and CB 1 , and more potent on FAAH. All compounds induced a response in the mouse "tetrad", particularly those with EC 50 Ͻ10 nM on VR 1 . However, the most potent compound, N-NЈ-di-(3-chloro-4-hydroxy)benzylarachidonamide (O-2093, ED 50 ϳ0.04 mg/kg), did not activate VR 1 or CB 1 receptors. Our findings suggest that VR 1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.

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Highly Selective CB1 Cannabinoid Receptor Ligands and Novel CB1/VR1 Vanilloid Receptor “Hybrid” Ligands

Cited by 113 publications

References 24 publications

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

Differential Effects of Δ⁹-Tetrahydrocannabinol and Methanandamide in CB1 Knockout and Wild-Type Mice

A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

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Highly Selective CB1 Cannabinoid Receptor Ligands and Novel CB1/VR1 Vanilloid Receptor “Hybrid” Ligands

Cited by 113 publications

References 24 publications

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

Differential Effects of Δ9-Tetrahydrocannabinol and Methanandamide in CB1 Knockout and Wild-Type Mice

A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

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Differential Effects of Δ⁹-Tetrahydrocannabinol and Methanandamide in CB1 Knockout and Wild-Type Mice