Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
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PMID:Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. 199 16

Two synthetic cannabinoids, WIN 55,212-2 {R-(+)-(2,3-dihydro-5-methyl-3-[{4-morpholinylmethyl]pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate} (5.0 and 10 mg/kg i.p.) and CP 55,940 {[1a,2-(R)-5-(1.1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} {[1a,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} (0.5 and 1.0 mg/kg i.p.), inhibited acetylcholine release in the rat hippocampus. The inhibition was prevented by the cannabinoid receptor antagonist, SR 141716A {N-(piperidin-1-yl)-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide} HCl, at the dose of 0.1 mg/kg i.p. Higher doses of SR 141716A (1.0 and 3.0 mg/kg i.p.) themselves increased hippocampal acetylcholine release, suggesting that acetylcholine output is tonically inhibited by endogenous cannabinoids. The results also suggest that the negative effects of marijuana on learning and memory may depend on cannabinoid receptor-mediated inhibition of acetylcholine release.
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PMID:Inhibition of hippocampal acetylcholine release by cannabinoids: reversal by SR 141716A. 918 41

Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and delta9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-delta9-THC dimethylheptyl (+)-11-OH-delta9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. Six analogs elicited pronounced and long lasting hypotension and bradycardia that were blocked by 3 mg/kg of SR141716A. The rank order of potency was (-)-11-OH-delta9-THC dimethylheptyl > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > THC > anandamide > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol, which correlated well with CB1 receptor affinity or analgesic potency (r = 0.96-0.99). There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-delta9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear.
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PMID:Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. 919 Aug 33

The putative endogenous cannabinoid, anandamide (0.2-2 mg/kg i.v.), decreased systemic blood pressure dose-dependently in anesthesized guinea pigs. These effects were prevented by the CB1 cannabinoid receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide x HCl] at the dose of 0.2 mg/kg i.v. The vasodepressor responses to anandamide were significantly potentiated and prolonged by a novel inhibitor of carrier-mediated anandamide transport, N-(4-hydroxyphenyl) arachidonylethanolamide (AM404) (10 mg/kg, i.v.). These results suggest that anandamide transport participates in terminating the vascular actions of anandamide.
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PMID:Potentiation of anandamide hypotension by the transport inhibitor, AM404. 938 89

The effect of delta9-tetrahydrocannabinol, the psychoactive principle of marijuana, and [R-(+)-(2,3-dihydro-5-methyl-3-[[4-morpholinylmethyl]pyrol[1,2,3-d e-]-1,4-benzoxazin-6y)(1-naphthalenyl)methanone monomethanesulfonate] (WIN 55,212-2), a synthetic cannabinoid receptor agonist, on the acetylcholine output in the medial-prefrontal cortex and hippocampus was studied by microdialysis in freely moving rats. The administration of delta9-tetrahydrocannabinol (1 and 5 mg/kg i.p.) and WIN 55,212-2 (5 and 10 mg/kg i.p.) produced a long lasting inhibition of acetylcholine release in both areas. The inhibitory effect of delta9-tetrahydrocannabinol and WIN 55,212-2 was suppressed in both areas by the specific cannabinoid CB1 receptor antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3carboxamide]HCl (SR 141716A), at the dose of 0.1 mg/kg i.p., per se ineffective to modify basal acetylcholine release. Most interestingly, SR 141716A alone at higher doses increased acetylcholine release both in the medial-prefrontal cortex (3 mg/kg i.p.) and hippocampus (1 and 3 mg/kg i.p.), suggesting that acetylcholine output is tonically inhibited by endogenous cannabinoids. Since the inhibitory effect of delta9-tetrahydrocannabinol is produced by doses within those relevant to human use of marijuana, our results suggest that the negative effects of the latter on cognitive processes may be explained by its ability to reduce acetylcholine release in the medial-prefrontal cortex and hippocampus. Conversely, cannabinoid receptor antagonists may offer potential treatments for cognitive deficits.
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PMID:Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A. 976 25

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.
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PMID:Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. 979 29

Anandamide is an endogenous cannabinoid receptor agonist with similar pharmacological effects as D9-tetrahydrocannabinol, the major psychoactive compound in marijuana. Because anandamide does inhibit long-term potentiation, and cannabinoid abuse is known to affect learning and memory, the effects of anandamide on recombinant AMPA glutamate receptor (GluR) subunit currents were studied in Xenopus oocytes. All subunit currents were not affected by SR-1 41716A (a selective CB1 cannabinoid receptor antagonist), but were blocked by the selective AMPA antagonist CNQX and were sensitive to anandamide. Anandamide directly inhibited kainate (KA) activated homomeric GluR1; GluR3 and heteromeric GluR1/3; GluR2/3 receptor currents with IC50 values of 161+/-19, 143+/-12, 148+/-10 and 241+/-107 microM, respectively. The sensitivity of all the subunits to anandamide was not significantly different. Anandamide inhibition was voltage-independent, specific, and could not be duplicated by arachidonic acid or WIN 55,212-2 mesylate. Furthermore, anandamide effects were potentiated by forskolin (an adenylyl cyclase stimulator) and 8-bromo-cAMP (a cAMP analog), whereas MDL-HCl (an adenylyl cyclase inhibitor) caused a reversal of anandamide inhibition of GluR receptor current. Anandamide inhibition appears to be mediated by cAMP synthesis, and may underlie the involvement of this brain cannabinoid agonist in the modulation of fast synaptic transmission in the CNS.
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PMID:Anandamide inhibition of recombinant AMPA receptor subunits in Xenopus oocytes is increased by forskolin and 8-bromo-cyclic AMP. 1054 24

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.
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PMID:Pharmacological evaluation of aerosolized cannabinoids in mice. 1088 13

Intravenous administration of the cannabinoid CB(1) receptor agonists (R-(+)-[2, 3-Dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), WIN 55,212-2 (10, 37.5, 75 and 150 microg/kg), and ((6aR)-trans-3-(1, 1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol), HU 210 (1 and 4 microg/kg) dose-dependently increased acetylcholine release in dialysates from the prefrontal cortex and the hippocampus of freely moving rats. Administration of the cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide]HCl, SR 141716A, at a dose that per se did not affect basal acetylcholine release (2. 5 microg/kg), prevented the increase of acetylcholine release by WIN 55,212-2 (150 microg/kg i.v.) or by HU 210 (4 microg/kg i.v.) in both areas. These data demonstrate that, at low i.v. doses, the synthetic cannabinoid CB(1) receptor agonists, WIN 55,212-2 and HU 210 stimulate cortical and hippocampal acetylcholine release.
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PMID:Cannabinoid CB(1) receptor agonists increase rat cortical and hippocampal acetylcholine release in vivo. 1092 24

The effects of chronic Delta(9)-tetrahydrocannabinol on cannabinoid receptor levels and receptor-G-protein coupling were investigated. Male Sprague-Dawley rats were infused continuously with low or high dose regimens of Delta(9)-tetrahydrocannabinol or vehicle for 4 days. Following treatment, rats were sacrificed for cannabinoid CB(1) receptor binding analysis or challenged with the cannabinoid CB(1) receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). The rats receiving Delta(9)-tetrahydrocannabinol exhibited antagonist-precipitated withdrawal signs. Each brain region (cerebellum, cortex, hippocampus and basal ganglia) from high-dose rats showed 30-70% decreases in [3H] (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxyphenyl)cyclohexanol (WIN55212-2) B(max) values, indicating receptor down-regulation. Most regions showed decreased WIN55212-2-stimulated [35S]guanosine-5'-O-3-thiotriphosphate (GTPgammaS) binding, indicating desensitization of cannabinoid CB(1) receptors. Additional receptor binding assays in cerebellar membranes showed a significantly greater decrease in agonist than in antagonist B(max) values, indicating a lower fraction of coupled receptors after treatment. Concentration-effect analysis of five agonists revealed that the treatment resulted in greater decreases in the efficacy of low-efficacy agonists.
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PMID:The effects of delta9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors. 1252 39


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