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

doi:10.1006/bbrc.2001.4354

Biochemical and Biophysical Research Communications

Volume 281, Issue 2, 23 February 2001, Pages 444-451

https://doi.org/10.1006/bbrc.2001.4354 Get rights and content

Abstract

Anandamide and the metabolically stabler analogs, (R)-1′-methyl-2′-hydroxy-ethyl-arachidonamide (Met-AEA) and N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide (arvanil), are CB₁ cannabinoid and VR₁ vanilloid receptors agonists. We synthesized 1′,1′-dimethylheptyl-arvanil (O-1839) and six other AEA analogs obtained by addition of either a hydroxy, cyano, or bromo group on the C-20 atom of 1,1′-dimethylpentyl-Met-AEA (O-1811, O-1812 and O-1860, respectively) or 1,1′-dimethylpentyl-arvanil (O-1856, O-1895 and O-1861, respectively). The compounds were tested for their (i) affinity for CB₁ and CB₂ receptors, (ii) capability to activate VR1 receptors, (iii) inhibitory effect on the anandamide hydrolysis and on the anandamide membrane transporter, and (iv) cannabimimetic activity in the mouse ‘tetrad’ of in vivo assays. O-1812 is the first ligand ever proven to be highly (500- to 1000-fold) selective for CB₁ vs both VR₁ and CB₂ receptors, while O-1861 is the first true “hybrid” agonist of CB₁/VR₁ receptors and a compound with potential therapeutic importance. The activities of the seven compounds in vivo did not correlate with their activities at either CB₁ or VR₁ receptors, thus suggesting the existence of other brain sites of action mediating some of their neurobehavioral actions in mice.

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More than 500 molecules have been identified as components of Cannabis sativa (C. sativa), of which the most studied is Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Several studies have suggested that Δ⁹-THC exerts diverse biological effects, ranging from fragmentation of DNA to behavioral disruptions. Currently, it is accepted that most of the pharmacological properties of Δ⁹-THC engage the activation of the cannabinoid receptors, named CB₁ and CB₂. Interestingly, multiple pieces of evidence have suggested that the cannabinoid receptors play an active role in the modulation of several diseases leading to the design of synthetic cannabinoid-like compounds. Advances in the development of synthetic CB₁ cannabinoid receptor selective agonists as therapeutical approaches are, however, limited. This review focuses on available evidence searched in PubMed regarding the synthetic CB₁ cannabinoid receptor selective agonists such as AM-1235, arachidonyl-2′ chloroethylamide (ACEA), CP 50,556–1 (Levonantradol), CP-55,940, HU-210, JWH-007, JWH-018, JWH-200 (WIN 55,225), methanandamide, nabilone, O-1812, UR-144, WIN 55,212-2, nabiximols, and dronabinol. Indeed, it would be ambitious to describe all available evidence related to the synthetic CB₁ cannabinoid receptor selective agonists. However, and despite the positive evidence on the positive results of using these compounds in experimental models of health disturbances and preclinical trials, we discuss evidence in regards some concerns due to side effects.
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Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice
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The objectives of this study were to characterize the discriminative stimulus effects of THC in FAAH knockout mice compared to wildtype controls, and to determine potential phenotypic differences in responding with cannabinoid agonists and endocannabinoid metabolic enzyme inhibitors. Specifically, dose–response determinations were conducted with THC, anandamide, O-1812 (a metabolically stable anandamide analog; Di Marzo et al., 2001), JZL184 (MAGL inhibitor; Long et al., 2009a), and JZL195 (dual FAAH/MAGL inhibitor; Long et al., 2009b). Challenge tests with the CB1 receptor antagonist rimonabant were conducted when appropriate.
A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ⁹-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose–response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB₁ receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184).
Cannabis and bioactive cannabinoids
2015, Studies in Natural Products Chemistry
The therapeutic use of Cannabis dates back to ancient times and this plant has been used for centuries as remedy for a large number of diseases. Today it is well known that biological activity of Cannabis is related to the endocannabinoid system (ECS), a complex signaling network that comprises classical cannabinoid receptors (CB1 and CB2), arachidonic acid-derived ligands, and enzymes degrading the endocannabinoids anandamide and 2-arachidonoyl glycerol, namely fatty acid amide hydrolase and monoacylglycerol lipase. The modulation of the ECS activity turned out to be a therapeutic promise in a wide range of diseases. A problem to the development of Cannabis and cannabinoid medications is the psychoactive property of natural or synthetic agonists, mediated by CB1 receptor. This review deals with the literature analysis of the important biological activities of Cannabis and the efforts aimed to the discovery of natural and nonnatural selective cannabinoids.
"Herbal incense": Designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays
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Citation Excerpt :
The TRPV1 protein is activated by excessive heat and pungent chemicals present in red hot chili peppers and mustard. For example, mice given the mixed AEA/TRPV1 derivative O-1839 (1,1-dimethylheptyl-arvanil), which has good efficacy for TRPV1, behaved in a “THC-like” manner in the tetrad test even though the affinity for CB1R was low (Ki > 200 nM) (Di Marzo et al., 2001). Additional testing, using rats discriminating between THC and vehicle, suggested that O-1839 did not mimic the discriminative stimulus effects of THC or the stimulus effects of a high-affinity CB1R (ki 3–5 nM) AEA derivative O-1812 [(R,5Z,8Z,11Z,14Z)-20-cyano-N-(1-hydroxypropan-2-yl)-16,16-dimethylicosa-5,8,11,14-tetraenamide]; THC and O-1812, on the other hand, exhibited cross-substitution and the effects were blocked by the selective CB1R inverse agonist/antagonist rimonabant (Wiley et al., 2004).
Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called “Spice”. The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar “subjective high” with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new “designer” cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics.
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Regular ArticleHighly Selective CB1 Cannabinoid Receptor Ligands and Novel CB1/VR1 Vanilloid Receptor “Hybrid” Ligands

Abstract

Pharmacol. Ther.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

FEBS Lett.

Pain

Trends Neurosci.

Biochem. Biophys. Res. Commun.

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

Science

Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

Nature

The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1)

Br. J. Pharmacol.

The capsaicin receptor: A heat-activated ion channel in the pain pathway

Nature

Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors

Proc. Natl. Acad. Sci. USA

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