Aviva Breuer

• Hebrew University of Jerusalem

Cannabidiol (CBD) is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. Here, we investigated whether HUF-101 (3, 10, and 30...

[This corrects the article DOI: 10.1371/journal.pone.0158779.].

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects i...

Bacterial populations communicate through the cell density-dependent mechanism of quorum sensing (QS). Vibrio harveyi, one of the best studied model organisms for QS, was used to explore effects of the synthetic cannabinoid HU-210 on QS and different QS-regulated physiological processes in bacteria. Analysis of QS-regulated bioluminescence in wild-...

Significance The significance of the results reported is in two areas. ( i ) Because the cannabinoid receptor type 2 (CB2) agonists seem to be general protective agents, HU-433, a new specific CB2 agonist, may be of major therapeutic importance. ( ii ) Enantiomers usually have different activity profiles. We report now that HU-433 and its enantiome...

Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat...

The endocannabinoid (eCB) system helps recovery following traumatic brain injury (TBI). Treatment with 2-arachidonoylglycerol (2-AG), a cerebral eCB ligand, was found to ameliorate the secondary damage. Interestingly, the fatty acid amino acid amide (FAAA) N-arachidonoyl-L-serine (AraS) exerts similar eCB dependent neuroprotective. The present stud...

Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB 1 and CB 2), as well as for activation of CB 1 -and CB 2 -mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., ca...

The interaction between two non-psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), which have been reported to act as a 5-hydroxytryptamine 1A (5-HT(1A)) agonist and antagonist, respectively, was evaluated. To evaluate the potential of CBG to reverse the anti-nausea, anti-emetic effects of CBD. In experiment 1, rats were pre-treat...

Experimental autoimmune encephalomyelitis (EAE) is a widely used model of multiple sclerosis (MS) and both conditions have been reported to exhibit reduced endocannabinoid activity. The purpose of this study was to address the effect of exogenously administered 2-arachidonoylglycerol (2AG), an endocannabinoid receptor ligand, on acute phase and chr...

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The ethanolamides of arachidonic, myristic and linoleic acids reduce bone marrow cell migration, while the 2-glyceryl esters of these acids enhance migration. Thus the 2 major endocannabinoids, anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol), whose structural difference lies in the nature of the end-group alone, work in op...

We have reviewed the effects of two endogenous cannabinoid constituents, anandamide and 2-Ara-G1, and of two synthetic cannabinoids, HU-211 and HU- 210. Anandamide partly parallels THC in most CNS activities; the lack of published data prevents comparison of 2-Ara-G1 with THC. Anandamide probably serves as a mediator in motor functions, in memory a...

Delta-9 tetrahydrocannabinol (Delta(9)-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Delta(9)-THC activates cannabinoid CB(1) and CB(2) receptors and induces psychoactive and peripheral effects. (-)-CBD possesses no, or very weak affinity for these receptors. We test...

(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiological effects of therapeutic importance. We have reported that CBD derivatives in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-...

Delta9-Tetrahydrocannabinol (Delta9-THC) and (-)-cannabidiol are major constituents of the Cannabis sativa plant with different pharmacological profiles: (-)-Delta9-tetrahydrocannabinol, but not (-)-cannabidiol, activates cannabinoid CB1 and CB2 receptors and induces psychoactive and peripheral effects. We have tested a series of (+)-cannabidiol de...

We have investigated the effect of 0.001 mg/kg delta(8)-tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in...

The endogenous cannabinoids N-arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are known to decrease intraocular pressure (IOP). Recently, a novel putative endogenous cannabinoid, noladin ether, was isolated in porcine and rat brains. In the present study, both the degradation of endogenous cannabinoids in ocular tissues and the effec...

Traumatic brain injury triggers the accumulation of harmful mediators that may lead to secondary damage. Protective mechanisms to attenuate damage are also set in motion. 2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid, identified both in the periphery and in the brain, but its physiological roles have been only partially clarified. Her...

Δ9-Tetrahydrocannabinol, the active principle in marijuana, is a cannabinoid receptor agonist. Both the crude drug and Δ9-tetrahydrocannabinol have been used as appetite promoters. The endogenous cannabinoid, arachidonoyl ethanolamide (anandamide), likewise a cannabinoid receptor agonist, has been shown to have the same effect. In contrast, the can...

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, e...

2-Arachidonylglycerol (2-AG) inhibits the production in vitro of tumor necrosis factor-α (TNF-α) by mouse macrophages, as well as in mice. It has no effect on the production of nitric oxide (NO). The effect on TNF-α is enhanced when 2-AG is administered together with 2-linoleylglycerol (2-Lino-G) and 2-palmitylglycerol (2-PalmG), an ‘entourage effe...

Two cannabinoid receptors have been identified: CB(1), present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present outside the CNS, in peripheral organs. There is evidence for the presence of CB(2)-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB(2)-specific agonis...

Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-...

Both aqueous and methanolic fractions derived from the Tibetan preparation PADMA-28 (a mixture of 22 plants) used as an anti-atherosclerotic agent, and which is non-cytolytic to a variety of mammalian cells, were found to strongly inhibit (1) the killing of epithelial cells in culture induced by 'cocktails' comprising oxidants, membrane perforating...

Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabi...

(-)-Delta9-Tetrahydrocannabinol ((-)-Delta9-THC) is the major active psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its derivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the neuron...

(-)-Δ⁹-Tetrahydrocannabinol ((-)-Δ⁹-THC) is the major active psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its derivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the neuronal canna...

The effect of Δ8-THC on experimental autoimmune encephalomyelitis (EAE) was examined. Δ8-THC is an analogue of Δ9-THC, the psychoactive component of marihuana. It is more stable and less psychotropic than Δ9-THC and like the latter it binds to the brain cannabinoid receptor. Two strains of rats were incolulated for EAE, and Δ8-THC (40 mg/kg) was ad...

1. In order to assess the presence of anxiolytic properties in cannabidiol (CBD) derivatives HU-219, HU-252 and HU-261, these drugs were tested in rats submitted to the elevated plus-maze model of anxiety. 2. Additional groups received diazepam or CBD. HU-219 (0.03-1 mg/kg) and CBD (5 mg/kg) significantly increased the percentage of open arm entrie...

The cannabimimetic activity of two enantiomeric pairs of compounds structurally different from the classical cannabinoids was evaluated in rats and pigeons, trained to discriminate between the presence and absence of (-)-delta-9-tetrahydrocannabinol (THC). One pair of enantiomers [compounds (+)-HU-249 and (-)-HU-250] has a 5-membered oxygen-contain...

Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibi...

Two strategies for the design of therapeutically useful cannabinoids have been combined to produce compounds with greatly increased antiinflammatory activity and with a low potential for adverse side effects. Enantiomeric cannabinoids with a carboxylic acid group at position 7 and with an elongated and branched alkyl sidechain at position 5' have b...

The 1,1-dimethylheptyl (DMH) homologue of 7-hydroxy-delta 6-tetrahydrocannabinol (3) is the most potent cannabimimetic substance reported so far. Hydrogenation of 3 leads to a mixture of the epimers of 5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol or to either the equatorial (7) or to the axial epimer (8), depending on the catalysts and cond...

The present overview covers various aspects of research going on in the Cannabis field in the Department of Natural Products at the Hebrew University. In the first part we discuss, and try to explain, the reason for the absence of the term Cannabis (and possibly also opium) in the Old Testament. In the second part we bring evidence that, contrary t...

The 1,1-dimethylheptyl tetrahydrocannabinol derivative (+)-(V) as well as its enantiomer (-)-(V) are prepared with high optical purities (> 99.8%) starting from both enantiomers of myrtenol (I).

The synthesis of the (2R,3R,4S,6R)-7/(2S,3S,4R,6S)-8 enantiomeric pair of benzofuran cannabinoids is reported together with the 1H and 13C NMR spectral parameters. In benzofuran 8 the configurational arrangement of ligated groups at the stereogenic C(3) atom (through which the terpene moiety is connected to the aromatic ring) is very similar to tha...

Pigeons, trained to discriminate between the presence or absence of delta 1-tetrahydrocannabinol (THC) (I) (0.56 mg/kg), were tested with (1S,4R)-delta 2-THC (II) (1-17.5 mg/kg), with the C-1 epimers of (4R)-delta 2-THC acetate, namely (1S,4R)-delta 2-THC acetate (IIIA) (3-17.5 mg/kg) and (1R,4R)-delta 2-THC acetate (IIIB) (1-17.5 mg/kg) and with t...

Pigeons, trained to discriminate between the presence or absence of Δ1-tetrahydrocannabinol (THC) (I) (0.56 mg/kg), were tested with (1S,4R)-Δ2-THC (II) (1–17.5 mg/kg), with the C-1 epimers of (4R)-Δ2-THC acetate, namely (1S,4R)-Δ2-THC acetate (IIIA) (3–17.5 mg/kg) and (1R,4R)-Δ2-THC acetate (IIIB) (1–17.5 mg/kg) and with the enantiomers of Δ3-THC...

The SAR of cannabimimetic activity in the cannabinoid series are reviewed with emphasis on the stereochemical requirements. Some new results are presented. The most important are that a, in humans, (-)-(1S)-delta-3-THC is much more active than (+)-(1R)-delta-3-THC; and b, with the 7-OH-delta-6-THC DMH enantiomers (32) and (33), the activity in seve...

N-Tetrahydrocannabinol (I) (A′-THC) isomerisiert sich in Gegenwart einer geeigneten Base zu den epimeren Az-THC (I I) und (III), wobei das Epimerenverhältnis von der Natur der Base und den Versuchsbedingungen abhängt (die Reaktion nach B unterliegt anfangs kinetischer Kontrolle; keine Ausb.-Angabe).

Base-catalysed double-bond isomerization offers a convenient, high-yield route to a variety of new cannabinoids, as well as to compounds of this group which are accessible with some difficulty. By this route we have obtained optically active Δ2-tetrahydrocannabinols and Δ3-tetrahydrocannabinols, the Δ6-isomer of cannabidiol, and other novel cannabi...