Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cannabinoid Receptor Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 865 records · Page 48Linked to original sources
PubMed2006

The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases.

How lipid transmitters move within and between cells to communicate signals remains an important and largely unanswered question. Integral membrane transporters, soluble lipid-binding proteins, and metabolic enzymes have all been proposed to collaboratively regulate lipid signaling dynamics in vivo. Assignment of the relative contributions made by each of these classes of proteins requires selective pharmacological agents to perturb their individual functions. Recently, LY2183240, a heterocyclic urea inhibitor of the putative endocannabinoid (EC) transporter, was shown to disrupt the cellular uptake of the lipid EC anandamide and promote analgesia in vivo. Here, we show that LY2183240 is a potent, covalent inhibitor of the EC-degrading enzyme fatty acid amide hydrolase (FAAH). LY2183240 inactivates FAAH by carbamylation of the enzyme's serine nucleophile. More global screens using activity-based proteomic probes identified several additional serine hydrolases that are also inhibited by LY2183240. These results indicate that the blockade of anandamide uptake observed with LY2183240 may be due primarily to the inactivation of FAAH, providing further evidence that this enzyme serves as a metabolic driving force that promotes the diffusion of anandamide into cells. More generally, the proteome-wide target promiscuity of LY2183240 designates the heterocyclic urea as a chemotype with potentially excessive protein reactivity for drug design.

Amidohydrolases↗
PubMed2003

Synthesis, in vitro evaluation, and intraocular pressure effects of water-soluble prodrugs of endocannabinoid noladin ether.

The poor aqueous solubility of 2-arachidonyl glyceryl ether (noladin ether) 2 hinders both pharmacological studies and pharmaceutical development. The synthesized mono- and diphosphate esters of noladin ether (4 and 6) considerably increased the aqueous solubility of noladin ether (>40000-fold), showed high stability against chemical hydrolysis in buffer solutions, and were rapidly converted to the parent drug via enzymatic hydrolysis. The monophosphate ester of noladin ether reduced intraocular pressure in normotensive rabbits.

Animals↗
PubMed2005

Molecular dynamics simulations of the endocannabinoid N-arachidonoylethanolamine (anandamide) in a phospholipid bilayer: probing structure and dynamics.

The phospholipid bilayer plays a central role in the lifecycle of the endogenous cannabinoid N-arachidonoylethanolamine (anandamide, 1). Compound 1 has been shown to be synthesized from lipids, to interact with the membrane-embedded cannabinoid CB1 receptor, to be transported to intracellular compartments, possibly via caveolae-related endocytosis, and finally, to be degraded by fatty acid amide hydrolase (FAAH), an integral membrane protein which has an active site that is accessed by 1 possibly via the bilayer. Because the anandamide system is intimately associated with the lipid milieu, information concerning the location of 1 in the phospholipid bilayer and the conformations it can adopt is important to our understanding of the mechanism of cannabinoid action at the molecular level. We report here an exploration of the properties of 1 in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) phospholipid bilayer via multi-nanosecond molecular dynamics simulations. Our results suggest that the polar headgroup of 1 resides at the lipid-water interface, specifically in the polar phospholipid headgroup region, whereas the nonpolar acyl chain of 1 extends into the hydrocarbon core of the membrane. Our analysis also indicates that (i) an elongated conformation of 1 is preferred in the DOPC bilayer environment; however, many other conformations of 1 are observed; (ii) hydrogen-bonding between the lipid (DOPC) and the headgroup of 1, although extensive, is quite short-lived; and (iii) the C-H bond order parameters for the acyl chain of 1 are low compared to order parameters typically seen for saturated acyl chains of fatty acids, and these order parameters decrease toward the bilayer center. The bilayer location for 1 revealed by these studies may be important for the interaction of 1 with membrane-embedded proteins such as the cannabinoid CB1 receptor and membrane-associated proteins such as FAAH.

Arachidonic Acids↗
PubMed2003

Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.

TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat) and the synthetic ligand 4alphaPDD. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5',6'-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone.

8,11,14-Eicosatrienoic Acid↗
PubMed2003

Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids.

Many types of neurons can release endocannabinoids that act as retrograde signals to inhibit neurotransmitter release from presynaptic terminals. Little is known, however, about the properties or role of such inhibition under physiological conditions. Here we report that brief bursts of presynaptic activity evoked endocannabinoid release, which strongly inhibited parallel fiber-to-Purkinje cell synapses in rat cerebellar slices. This retrograde inhibition was triggered by activation of either postsynaptic metabotropic or ionotropic glutamate receptors and was restricted to synapses activated with high-frequency bursts. Thus, endocannabinoids allow neurons to inhibit specific synaptic inputs in response to a burst, thereby dynamically fine-tuning the properties of synaptic integration.

Animals↗
PubMed2004

A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity.

Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.

Animals↗
PubMed2004

Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus.

In hippocampal pyramidal cells, a rise in Ca(2+) releases endocannabinoids that activate the presynaptic cannabinoid receptor (CB1R) and transiently reduce GABAergic transmission-a process called depolarization-induced suppression of inhibition (DSI). The mechanism that limits the duration of endocannabinoid action in intact cells is unknown. Here we show that inhibition of cyclooxygenase-2 (COX-2), not fatty acid amide hydrolase (FAAH), prolongs DSI, suggesting that COX-2 limits endocannabinoid action.

Amidohydrolases↗
PubMed2005

Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus.

The functions of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid found in the brain, remain largely unknown. Here we show that two previously unknown inhibitors of monoacylglycerol lipase, a presynaptic enzyme that hydrolyzes 2-AG, increase 2-AG levels and enhance retrograde signaling from pyramidal neurons to GABAergic terminals in the hippocampus. These results establish a role for 2-AG in synaptic plasticity and point to monoacylglycerol lipase as a possible drug target.

Aniline Compounds↗
PubMed2006

Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration.

The hypothalamic paraventricular nucleus (PVN) is a major integrative site for the control of homeostasis, including energy balance, through coordinated regulation of neuroendocrine and autonomic outputs. However, cross-talk regulation of PVN neuroendocrine and preautonomic systems is poorly understood. The stress response invokes the coordinated control of motor, hormonal, and vegetative systems to establish homeostasis after an environmental perturbation. Elevated stress levels of circulating glucocorticoids give rise to multiple, complex physiological effects. The complexity of the glucocorticoid actions is caused by the wide range of glucocorticoid target tissues and to the broad time scale over which the actions occur. Recent studies have revealed rapid glucocorticoid actions in the hypothalamus that may provide an integrative signal linking stress with the regulation of energy and fluid homeostasis. Glucocorticoids inhibit PVN and supraoptic nucleus neurons by stimulating a rapid synthesis and retrograde release of endocannabinoids, which suppress synaptic excitation through presynaptic CB1 receptor activation. The glucocorticoid-induced endocannabinoid synthesis is mediated apparently by a novel membrane-associated glucocorticoid receptor found in multiple subpopulations of hypothalamic neuroendocrine cells. It may, therefore, represent a mechanism for rapid glucocorticoid control of activity among different neuroendocrine systems to coordinate a global response to stress. In support of this, leptin, a circulating adipose signal that regulates food intake and energy expenditure through central actions, blocks the glucocorticoid-mediated endocannabinoid release in the PVN. This represents a means by which the regulation of stress and feeding may interface in the PVN, thus providing a possible mechanism for the integration of multiple homeostatic functions.

Animals↗
PubMed2002

Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol.

Endocannabinoids are implicated in appetite and body weight regulation. In rodents, anandamide stimulates eating by actions at central CB1 receptors, and hypothalamic endocannabinoids may be under the negative control of leptin. However, changes to brain endocannabinoid levels in direct relation to feeding or changing nutritional status have not been investigated. We measured anandamide and 2-arachidonoyl glycerol (2-AG) levels in feeding-associated brain regions of rats, during fasting, feeding of a palatable food, or after satiation. Endocannabinoid levels were compared to those in rats fed ad libitum, at a point in their daily cycle when motivation to eat was absent. Fasting increased levels of anandamide and 2-AG in the limbic forebrain and, to a lesser extent, of 2-AG in the hypothalamus. By contrast, hypothalamic 2-AG declined as animals ate. No changes were detected in satiated rats. Endocannabinoid levels in the cerebellum, a control region not directly involved in the control of food intake, were unaffected by any manipulation. As 2-AG was most sensitive to variation during feeding, and to leptin regulation in a previous study, we examined the behavioural effects of 2-AG when injected into the nucleus accumbens shell, a limbic forebrain area strongly linked to eating motivation. 2-AG potently, and dose-dependently, stimulated feeding. This effect was attenuated by the CB1 receptor antagonist SR141716. These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2-AG in particular, during fasting and feeding. The nature of these effects supports a role for endocannabinoids in the control of appetitive motivation.

Animals↗
PubMed2003

Endocannabinoids protect the rat isolated heart against ischaemia.

1 The purpose of this study was to determine whether endocannabinoids can protect the heart against ischaemia and reperfusion. 2 Rat isolated hearts were exposed to low-flow ischaemia (0.5-0.6 ml min(-1)) and reperfusion. Functional recovery as well as CK and LDH overflow into the coronary effluent were monitored. Infarct size was determined at the end of the experiments. Phosphorylation levels of p38, ERK1/2, and JNK/SAPK kinases were measured by Western blots. 3 None of the untreated hearts recovered from ischaemia during the reperfusion period. Perfusion with either 300 nM palmitoylethanolamide (PEA) or 300 nM 2-arachidonoylglycerol (2-AG), but not anandamide (up to 1 micro M), 15 min before and throughout the ischaemic period, improved myocardial recovery and decreased the levels of coronary CK and LDH. PEA and 2-AG also reduced infarct size. 4 The CB(2)-receptor antagonist, SR144528, blocked completely the cardioprotective effect of both PEA and 2-AG, whereas the CB(1)-receptor antagonist, SR141716A, blocked partially the effect of 2-AG only. In contrast, both ACEA and JWH015, two selective agonists for CB(1)- and CB(2)- receptors, respectively, reduced infarct size at a concentration of 50 nM. 5 PEA enhanced the phosphorylation level of p38 MAP kinase during ischaemia. PEA perfusion doubled the baseline phosphorylation level of ERK1/2, and enhanced its increase upon reperfusion. The cardioprotective effect of PEA was completely blocked by the p38 MAP kinase inhibitor, SB203580, and significantly reduced by the ERK1/2 inhibitor, PD98059, and the PKC inhibitor, chelerythrine. 6 In conclusion, endocannabinoids exert a strong cardioprotective effect in a rat model of ischaemia-reperfusion that is mediated mainly through CB(2)-receptors, and involves p38, ERK1/2, as well as PKC activation.

Amides↗
PubMed2003

Manipulation of the endocannabinoid system by a general anaesthetic.

An article appearing in this issue of the British Journal of Pharmacology shows for the first time that the general anaesthetic propofol inhibits one of the enzymes catalysing endocannabinoid hydrolysis and inactivation, the fatty acid amide hydrolase, thereby enhancing the brain levels of anandamide and 2-arachidonoylglycerol in mouse brain. The authors provide evidence that this effect of propofol underlies part of the sedative effects of this compound. The importance of these findings in the light of the likely role of the endocannabinoid system in the control of sleep-wake cycles, and of the possibility of developing therapeutic drugs from substances that manipulate endocannabinoid levels, is discussed.

Anesthesia, General↗
PubMed2003

The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase.

1. Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. 2. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. 3. In vitro, propofol is a competitive inhibitor (IC(50) 52 micro M; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. 4. Pretreatment of mice with the CB(1) receptor antagonist SR141716 (1 mg kg(-1), i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB(1) receptor agonist, Win 55212-2 (1 mg kg(-1), i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB(1) receptor activity contributes to the sedative properties of propofol. 5. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development.

Amidohydrolases↗
PubMed2004

Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA).

1. We have investigated the vascular effects of N-arachidonoyl-dopamine (NADA), a novel endocannabinoid/vanilloid. NADA caused vasorelaxant effects comparable to those of anandamide in small mesenteric vessels (G3), the superior mesenteric artery (G0) and in the aorta. 2. In G3, addition of N(G)-nitro-l-arginine methyl ester (300 microm) or the dopamine (D(1)) receptor antagonist (SCH23390, 1 microm) did not affect responses to NADA. In the presence of 60 mm KCl, after de-endothelialisation, or after K(+) channel inhibition with charybdotoxin (100 nm) and apamin (500 nm), relaxant responses to NADA were inhibited. 3. In G3, pretreatment with the vanilloid receptor (VR) agonist capsaicin (10 microm) or the VR antagonist capsazepine (10 microm) reduced vasorelaxation to NADA. 4. In G3, application of the CB(1) antagonist SR141716A at 1 microm but not 100 nm reduced the potency of NADA. Another CB(1) antagonist, AM251 (100 nm and 1 microm), did not affect vasorelaxation to NADA. After endothelial denudation, SR141716A (1 microm) did not reduce the responses further. A combination of capsaicin and SR141716A (1 microm) reduced vasorelaxation to NADA further than with capsaicin pretreatment alone. The novel endothelial cannabinoid (CB) receptor antagonist O-1918 opposed vasorelaxation to NADA in G3. 5. In the superior mesenteric artery (G0), vasorelaxation to NADA was not dependent on an intact endothelium and was not sensitive to O-1918, but was sensitive to capsaicin and SR141716A or AM251 (both 100 nm). 6. The results of the present study demonstrate for the first time that NADA is a potent vasorelaxant. In G3, the effects of NADA are mediated by stimulation of the VR and the novel endothelial CB receptor, while in G0, vasorelaxation is mediated through VR(1) and CB(1) receptors.

Animals↗
PubMed2004

Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE).

Depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE) are two related forms of short-term synaptic plasticity of GABAergic and glutamatergic transmission, respectively. They are induced by calcium concentration increases in postsynaptic cells and are mediated by the release of a retrograde messenger, which reversibly inhibits afferent synapses via presynaptic mechanisms. We review here: 1. The evidence accumulated during the 1990s that has led to the conclusion that DSI/DSE rely on retrograde signaling. 2. The more recent research that has led to the identification of endocannabinoids as the retrograde messengers responsible for DSI/DSE. 3. The possible mechanisms by which presynaptic type 1 cannabinoid receptors reduce synaptic efficacy during DSI/DSE. 4. The possible modes of induction of DSI/DSE by physiological activity patterns, and the partially conflicting evaluations of the calcium concentration increases required for cannabinoid synthesis. 5. Finally, the relation between DSI/DSE and other forms of long- and short-term synaptic inhibition, which were more recently associated with the production of endocannabinoids by postsynaptic cells. We conclude that recent studies on DSI/DSE have uncovered a specific and original mode of action for endocannabinoids in the brain, and that they have opened new avenues to understand the role of retrograde signaling in central synapses.

Animals↗
PubMed2005

The effects of Delta9-tetrahydrocannabinol in rat mesenteric vasculature, and its interactions with the endocannabinoid anandamide.

1 Delta9-tetrahydrocannabinol (THC) produces varying effects in mesenteric arteries: vasorelaxation (third-order branches, G3), modest vasorelaxation (G2), no effect (G1) and vasoconstriction (the superior mesenteric artery, G0). 2 In G3, vasorelaxation to THC was inhibited by pertussis toxin, but was unaffected by the CB1 receptor antagonist, AM251 (1 microM), incubation with the TRPV1 receptor agonist capsaicin (10 microM, 1 h), the TRPV1 receptor antagonist capsazepine (10 microM) or de-endothelialisation. 3 In G3, vasorelaxation to THC was inhibited by high K+ buffer, and by the following K+ channel inhibitors: charybdotoxin (100 nM), apamin (500 nM) and barium chloride (30 microM), but not by 4-aminopyridine, glibenclamide or tertiapin. 4 In G3, THC (10 and 100 microM) inhibited the contractile response to Ca2+ in a Ca2+-free, high potassium buffer, indicating that THC blocks Ca2+ influx. 5 In G0, the vasoconstrictor responses to THC were inhibited by de-endothelialisation and SR141716A (100 nM), but not by the endothelin (ET(A)) receptor antagonist FR139317 (1 microM).THC (1 and 10 microM) antagonised vasorelaxation to anandamide in G3 but not G0. THC did not antagonise the noncannabinoid verapamil, capsaicin or the CB1 receptor agonist CP55,940. 6 THC (10 and 100 microM) inhibited endothelium-derived relaxing factor (EDHF)-mediated responses to carbachol in a manner similar to the gap junction inhibitor 18alpha-glycyrrhetinic acid. 7 These data show that THC causes vasorelaxation through activation of K+ channels and inhibition of Ca2+ channels, and this involves non-CB1, non-TRPV1 but G-protein-coupled receptors. In G0, THC does not cause relaxation and at high concentrations causes contractions. Importantly, THC antagonises the effects of anandamide, possibly through inhibition of EDHF activity.

Animals↗