Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556.

Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

Novel Synthesis of C-Methylated Phytocannabinoids Bearing Anti-inflammatory Properties.

There is growing interest in non-psychoactive phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), and cannabichromene, as potential leads for novel therapeutic agents. In this study, we report on the development of new derivatives in which we methylated either position 4 of olivetol or the phenolic positions of olivetol, or both. We introduce a refinement on previously reported chemical procedures for phytocannabinoid derivatization as well as the biological evaluation of all derivatives in anti-inflammatory in vivo models. Compounds such as the CBD derivative, 2 and the CBG derivative, 11, significantly reduced cytokine levels when compared to their parent compounds. Moreover, both of these derivatives proved to be as potent as dexamethasone for the inhibition of IL-1ß. We believe that these new derivatives, as described herein, can be further developed as novel drug candidates for inflammatory conditions.

Antinociceptive effects of HUF-101, a fluorinated cannabidiol derivative.

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 30mg/kg), a fluorinated CBD analogue, would induce antinociceptive effects. HUF-101 effects were compared to those induced by CBD (10, 30, and 90mg/kg) and the cannabinoid CB1/2 receptor agonist WIN55,212-2 (1, 3, and 5mg/kg). These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: hot plate, acetic acid-induced writhing, and carrageenan-induced inflammatory hyperalgesia. To evaluate the involvement of CB1 and CB2 receptors in HUF-101 and CBD effects, mice received the CB1 receptor antagonist AM251 (1 or 3mg/kg) or the CB2 receptor antagonist AM630 (1 or 3mg/kg) 30min before HUF-101, CBD, or WIN55,212-2. In the hot plate test, HUF-101 (30mg/kg) and WIN55,212-2 (5mg/kg) induced antinociceptive effects, which were attenuated by the pretreatment with AM251 and AM630. In the abdominal writhing test, CBD (30 and 90mg/kg), HUF-101 (30mg/kg), and WIN55,212-2 (3 and 5mg/kg) induced antinociceptive effects indicated by a reduction in the number of writhing. Whereas the pretreatment with AM630 did not mitigate the effects induced by any drug in this test, the pretreatment with AM251 attenuated the effect caused by WIN55,212-2. In the carrageenan-induced hyperalgesia test, CBD (30 and 90mg/kg), HUF-101 (3, 10 and 30mg/kg) and WIN55,212-2 (1mg/kg) decreased the intensity of mechanical hyperalgesia measured by the electronic von Frey method. The effects of all compounds were attenuated by the pretreatment with AM251 and AM630. Additionally, we evaluated whether HUF-101 would induce the classic cannabinoid CB1 receptor-mediated tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception). Unlike WIN55,212-2, CBD and HUF-101 did not induce the cannabinoid tetrad. These findings show that HUF-101 produced antinociceptive effects at lower doses than CBD, indicating that the addition of fluoride improved its pharmacological profile. Furthermore, some of the antinociceptive effects of CBD and HUF-101 effects seem to involve the activation of CB1 and CB2 receptors.

Correction: Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects.

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

Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects.

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 in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4'-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.

Effect of the synthetic cannabinoid HU-210 on quorum sensing and on the production of quorum sensing-mediated virulence factors by Vibrio harveyi.

BACKGROUND: 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. RESULTS: Analysis of QS-regulated bioluminescence in wild-type and mutant strains of V. harveyi revealed that HU-210 affects the autoinducer-2 (AI-2) pathway, one of three known QS cascades of V. harveyi. Furthermore, QS-mediated biofilm formation and swimming motility in the mutant strain BB152 (AI-1(-), AI-2(+)) were significantly reduced in the presence of HU-210. HU-210 inhibited QS-mediated virulence factor production without any inhibitory effect on bacterial growth. It also alters the expression of several genes, which are regulated by QS, specifically downregulating the genes of the AI-2 QS cascade. CONCLUSION: First evidence is being provided for interference of bacterial signal-transduction systems by a synthetic cannabinoid. The effect of HU-210 was specific to the AI-2 cascade in V. harveyi. AI-2 is known as a "universal autoinducer" and interference with its activity opens a broad spectrum of applications for synthetic cannabinoids in future research as a potential anti-QS agent.

CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency.

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ(9)-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3-4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [(3)H]CP55,940 displacement and its effect on [(35)S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [(35)S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.

Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.

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 mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femurs from rats given a mixture of CBD and Δ(9) -tetrahydrocannabinol (THC) for 8 weeks were markedly increased by CBD. This effect is not shared by THC (the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks postfracture followed by attenuation of the CBD effect at 8 weeks. Using micro-computed tomography (µCT), the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier transform infrared (FTIR) spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.

Palmitoyl Serine: An Endogenous Neuroprotective Endocannabinoid-Like Entity After Traumatic Brain Injury.

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 study aimed to investigate the effects of the FAAA palmitoyl-serine (PalmS) following TBI. We utilized the TBI model in mice to examine the therapeutic potential of PalmS, injected 1 h following closed head injury (CHI). We followed the functional recovery of the injured mice for 28 days post-CHI, and evaluated cognitive and motor function, lesion volume, cytokines levels, molecular signaling, and infarct volume at different time points after CHI. PalmS treatment led to a significant improvement of the neurobehavioral outcome of the treated mice, compared with vehicle. This effect was attenuated in the presence of eCBR antagonists and in CB2-/- mice, compared to controls. Unexpectedly, treatment with PalmS did not affect edema and lesion volume, TNFα and IL1ß levels, anti-apoptotic mechanisms, nor did it exert improvement in cognitive and motor function. Finally, co-administration of PalmS, AraS and 2-AG, did not enhance the effect of the individual drugs. We suggest that the neuroprotective action of PalmS is mediated by indirect activation of the eCB receptors following TBI. One such mechanism may involve receptor palmitoylation which has been reported to result in structural stabilization of the receptors and to an increase in their activity. Further research is required in order to establish this assumption.

Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis.

BACKGROUND AND PURPOSE: 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 chronic disability in EAE. EXPERIMENTAL APPROACH: Acute and chronic EAE models were induced in susceptible mice and 2AG-treatment was applied for 14 days from day of disease induction. KEY RESULTS: 2AG-treatment ameliorated acute phase of disease with delay of disease onset in both EAE models and reduced disease mortality and long-term (70 days post-induction) clinical disability in chronic EAE. Reduced axonal pathology in the chronic EAE- (p<0.0001) and increased activation and ramification of microglia in the 2AG-treated acute EAE- (p<0.05) model were noticed. The latter was accompanied by a 2- to 4-fold increase of the M2-macrophages in the perivascular infiltrations (p<0.001) of the 2AG-treated animals in the acute (day 22), although not the chronic (day 70), EAE model. Expression of cannabinoid receptors 1 (CB1R) and 2 (CB2R) was increased in 2AG-treated animals of acute EAE vs. controls (p<0.05). In addition, ex vivo viability assays exhibited reduced proliferation of activated lymph node cells when extracted from 2AG-treated EAE animals, whereas a dose-dependent response of activated lymphocytes to 2AG-treatment in vitro was noticed. CONCLUSION AND IMPLICATIONS: Our data indicate for the first time that 2AG treatment may provide direct (via CBRs) and immune (via M2 macrophages) mediated neuroprotection in EAE.

Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol (CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews.

RATIONALE: 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. OBJECTIVE: To evaluate the potential of CBG to reverse the anti-nausea, anti-emetic effects of CBD. MATERIALS AND METHODS: In experiment 1, rats were pre-treated with CBG (0.0, 1, 5, and 10 mg/kg, ip), 15 min prior to being treated with CBD (experiment 1a: VEH or 5 mg/kg, ip) or 8-OH-DPAT (experiment 1b: VEH or 0.01 mg/kg, ip). Thirty minutes later, all rats received a pairing of 0.1% saccharin solution and LiCl (20 ml/kg of 0.15 M, ip). Seventy-two hours later, the rats received a drug-free taste reactivity test with saccharin to evaluate the effects of the treatments on the establishment of conditioned gaping reactions (a model of nausea). As well, conditioned saccharin avoidance was measured. In experiment 2, Suncus murinus were injected with CBG (5 mg/kg, ip) or VEH 15 min prior to CBD (5 mg/kg) or VEH and 30 min later were injected with LiCl (60 ml/kg of 0.15 M, i.p.), and the number of vomiting episodes were measured. RESULTS: CBD (5 mg/kg) suppressed conditioned gaping in rats and vomiting in shrews, which were reversed by pre-treatment with all doses of CBG. CBG also prevented the anti-nausea effects of 8-OH-DPAT. CONCLUSIONS: Interactions between moderate doses of CBG and CBD may oppose one another at the 5-HT(1A) receptor in the regulation of nausea and vomiting.

Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation.

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 opposite directions. The endocannabinoid arachidonoyl serine, a vasodilator, also reduces migration. The effect of 2-AG is mediated, in part at least, through the cannabinoid receptors, while the effect of anandamide, as well as the rest of the compounds assayed, are not mediated through them. Almost all cannabinoids tested, including anandamide and 2-AG, lead to approximate doubling of CFU-GEMM (colony-forming unit: granulocyte, erythrocyte, macrophage, megakaryocyte) colonies. The effect of anandamide is considerably more potent than that of 2-AG. A surprising dose-response increase of erythroid cells is noted in cultures with the ester cannabinoids (in the absence of the cytokine erythropoietin), while a considerable dose-response augmentation of megakaryocytes is noted in cultures with the ethanolamide cannabinoids (in the presence of erythropoietin). This is suggestive of some cross-talk between two different regulatory systems, one governed by glycoprotein ligands and the other by endocannabinoids.

Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors.

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 tested a series of (+)- and (-)-CBD derivatives for central and peripheral effects in mice. None of the (-)-CBD derivatives were centrally active, yet most inhibited intestinal motility. Of the five (+)-CBD derivatives, all with CB(1) receptor affinity, only (+)-7-OH-CBD-DMH (DMH=1,1-dimethylheptyl), acted centrally, while all five arrested defecation. The effects of (+)-CBD-DMH and (+)-7-OH-CBD-DMH were inhibited by the CB(1) receptor antagonist SR141716. The CB(2) receptor antagonist SR144528, and the vanilloid TRPV1 receptor antagonist capsazepine, had no influence. Further, the (-)-CBD derivatives (-)-7-COOH-CBD and (-)-7-COOH-CBD-DMH, displayed antiinflammatory activity. We suggest that (+)-CBD analogues have mixed agonist/antagonist activity in the brain. Second, (-)-CBD analogues which are devoid of cannabinoid receptor affinity but which inhibit intestinal motility, suggest the existence of a non-CB(1), non-CB(2) receptor. Therefore, such analogues should be further developed as antidiarrheal and/or antiinflammatory drugs. We propose to study the therapeutic potential of (-)- and (+)-CBD derivatives for complex conditions such as inflammatory bowel disease and cystic fibrosis.

Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors.

(-)-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-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series. The starting materials were the respective CBD enantiomers and their DMH homologs. The binding of these compounds to the CB(1) and CB(2) cannabinoid receptors are compared. Surprisingly, contrary to the compounds in the (-) series, which do not bind to the receptors, most of the derivatives in the (+) series bind to the CB(1) receptor in the low nanomole range. Some of these compounds also bind weakly to the CB(2) receptor.

(+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only.

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 derivatives, namely, (+)-cannabidiol-DMH (DMH-1,1-dimethylheptyl-), (+)-7-OH-cannabidiol-DMH, (+)-7-OH- cannabidiol, (+)-7-COOH- cannabidiol and (+)-7-COOH-cannabidiol-DMH, for central and peripheral (intestinal, antiinflammatory and peripheral pain) effects in mice. Although all (+)-cannabidiols bind to cannabinoid CB1 and CB2 receptors, only (+)-7-OH-cannabidiol-DMH was centrally active, while all (+)-cannabidiol analogues completely arrested defecation. The effects of (+)-cannabidiol-DMH and (+)-7-OH-cannabidiol-DMH were partially antagonized by the cannabinoid CB1 receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716), but not by the cannabinoid CB2 receptor antagonist N-[-(1S)-endo-1,3,3-trimethil bicyclo [2.2.1] heptan-2-yl-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), and had no effect on CB1(-/-) receptor knockout mice. (+)-Cannabidiol-DMH inhibited the peripheral pain response and arachidonic-acid-induced inflammation of the ear. We conclude that centrally inactive (+)-cannabidiol analogues should be further developed as antidiarrheal, antiinflammatory and analgesic drugs for gastrointestinal and other peripheral conditions.

Very low doses of delta 8-THC increase food consumption and alter neurotransmitter levels following weight loss.

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 food intake compared with controls (P<.001). This effect was reversed by the antagonist (P<.01). In the long-term schedule a 22% increase in intake (P<.05) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity (P<.05). Cognitive function showed a tendency to improve (P<.06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<.01, and P<.05, respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<.01) and the hippocampus (P<.01, P<.05), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. Delta(8)-THC increased food intake significantly more (P<.05) than did delta(9)-THC, while performance and activity were similar. Thus, delta(8)-THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders.

Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid.

PURPOSE: 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 effect on IOP of 2-AG and noladin ether were compared. METHODS: The rates of enzymatic degradation for AEA, 2-AG, and noladin ether were determined in bovine cornea and iris-ciliary body homogenates. 2-AG and noladin ether were dissolved in either hydroxypropyl-beta-cyclodextrin (HP-beta-CD) or propylene glycol and administered unilaterally to the rabbit eye. IOPs were measured in the treated and untreated eyes. The CB1 receptor antagonist AM251 was administered topically 15 minutes before the cannabinoids to investigate whether CB1 receptors mediate the effect on IOP produced by 2-AG and noladin ether. RESULTS: Noladin ether degraded more slowly than either 2-AG or AEA in the iris-ciliary body and cornea homogenates. The effect on IOP of 2-AG was biphasic (i.e., an initial increase in IOP followed by a reduction in the treated eye). Noladin ether decreased IOP immediately after topical administration, and no initial IOP increase was observed in the treated eye. The CB1 receptor antagonist AM251 (25 micro g) blocked the effect on IOP of noladin ether but did not affect the action of 2-AG. CONCLUSIONS: Topical administration of the novel putative endogenous cannabinoid noladin ether decreased IOP in rabbits. This IOP reduction was most probably mediated through the CB1 receptor. The effect on IOP of noladin ether differed from those of the known endogenous cannabinoids AEA and 2-AG, probably because of its more stable chemical structure.