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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aminoalkylindoles (AAIs) are structurally dissimilar from the classical cannabinoids (CCs), however, both AAIs and CCs appear to bind at the same site on the cannabinoid receptor. To obtain better insights on the structural correlation between AAIs and CCs, we have studied the conformational properties of the potent cannabimimetic AAI WIN 55212-2 and its inactive analogs using high resolution 2D NMR spectroscopy in combination with computer-assisted molecular modeling. The pharmacophoric similarities between the AAIs and the CCs were then investigated using superimposition techniques. The absolute stereochemistries of the biologically active enantiomer (-)HHC were used as superimposition points and considered as internal controls in order to test the molecular principles guiding this experiment. Our results show that the model is congruent with a superimposition in which the naphthoyl, morpholino and 3-keto groups in the AAI, respectively correspond to the side chain, cyclohexanol OH and phenolic OH of HHC. A good fit is obtained when the two biologically active antipodes are superimposed. Conversely, the fit is poor if the inactive AAI enantiomer is superimposed on the active HHC enantiomer. It can also be seen that in such an orientation a certain deviation of the C-ring from the plane of the phenol ring of the tricyclic HHC component and of the morpholinyl portion from the plane of the indole ring of WIN 55212-2 is essential for cannabimimetic activity. The inactive enantiomer WIN 55212-3 has its respective components aligned in the opposite quadrant. By comparing the stereoelectronic features of representative AAIs and CCs, we have developed a model which may help to uncover the pharmacophoric requirements of the AAIs and serve as a basis for future SAR and drug design.
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PMID:Common cannabimimetic pharmacophoric requirements between aminoalkyl indoles and classical cannabinoids. 777 20

Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (IA) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of IA. Specific activators of PKA produced a negative shift in voltage dependence of IA, whereas PKA inhibitors produced a positive shift in IA voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in IA induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in IA voltage dependence. This partial effect of PKA inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of IA.
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PMID:Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium "A-current" in cultured rat hippocampal neurons. 777 35

The neuronal cannabinoid receptor clone was expressed of saturable [3H]WIN 55,212-2 binding sites. Co-expression of the cannabinoid receptor with cRNA coding for the G-protein-gated inwardly rectifying K+ channel (GIRK1) resulted in oocytes exhibiting large inward K+ currents in response to the cannabinoid agonist WIN 55,212-2. The activation of the potassium current by WIN 55,212-2 was dose-dependent with an EC50 of 630 nM. These results suggest that activation of inwardly rectifying K+ channels may be an additional effector mechanism for brain cannabinoid receptors.
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PMID:Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. 777 6

In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 and WIN 55,212. The tolerance induced by repetitive administration of CP 55,940 was substantial. The ED50 for CP 55,940 was shifted 102 fold for spontaneous activity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tolerance to delta 9-THC and WIN 55,212 was observed in CP 55,940 chronically treated mice. These findings indicate that cross-tolerance develops between delta 9-THC, CP 55,940 and WIN 55,212 and that these agents have some actions in common. However, quantitative differences in their development of cross-tolerance suggests that all of their actions may not be identical.
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PMID:Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212. 799 50

Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significance. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, levonantradol and WIN 55,212-2) on cultured neurons from hippocampus, a brain region that exhibits high cannabinoid receptor density. The electrophysiological effects of cannabinoids were determined by whole-cell patch clamp recordings of voltage-dependent potassium currents. The voltage dependence of the rapidly inactivating potassium A current (IA), characteristic of hippocampal neurons, was significantly altered in a concentration-dependent manner by cannabinoid analogs. Decreased inactivation, which led to an increased activation of IA near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on IA while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid analogs was similar to that observed with respect to binding at cannabinoid receptors in brain membranes. The concentration-related effectiveness of cannabinoid analogs in modulating IA was similar to their potency in stimulating low Km GTPase in cell membranes isolated from the cannabinoid receptor-rich dentate gyrus. These data support the conclusion that cannabinoid effects on IA are mediated through G-protein-coupled receptors. This cannabinoid-induced shift in the voltage dependence of IA could serve to counteract fast, transient, depolarizing events such as action potentials and synaptic currents in hippocampal neurons.
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PMID:Cannabinoids modulate potassium current in cultured hippocampal neurons. 808 16

Anandamide (arachidonylethanolamide) is a compound recently isolated from porcine brain as a putative endogenous ligand at cannabinoid receptors. The present studies examined the effects of anandamide on cannabinoid receptor binding sites and adenylyl cyclase in rat brain membranes. Receptor binding experiments, conducted at 25 degrees for 90 min, apparently resulted in significant degradation of anandamide, since anandamide (10 microM) had little effect on [3H]WIN 55212-2 binding in cerebellar membranes. Addition of the general serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF) protected against this degradation, resulting in an IC50 value of 90 nM for anandamide versus [3H]WIN 55212-2 binding. Anandamide inhibited adenylyl cyclase in cerebellar membranes in a GTP-dependent manner, exhibiting a maximal inhibition level slightly less than that of WIN 55212-2 and CP-55,940, with an IC50 value of 1.9 microM. The effect of anandamide on adenylyl cyclase was region-specific, with maximal inhibition occurring in cerebellum and striatum. These results suggest that anandamide acts at G-protein-coupled cannabinoid receptors in brain with properties similar to those of exogenous cannabinoids.
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PMID:Effects of anandamide on cannabinoid receptors in rat brain membranes. 812 47

As previously reported by this laboratory, an endogenous factor capable of inhibiting the specific binding of the radiolabeled cannabinoid agonist [3H]CP-55940 to its receptor can be released from nerve terminals in response to an influx of Ca++ induced by an ionophore (Evans et al., 1992). In the present report, we provide evidence that the endogenous ligand for the cannabinoid receptor can be released in response to a depolarizing stimulus (75 mM K+) in the presence of extracellular Ca++. K(+)-evoked release was not observed in the absence of extra-cellular Ca++ and was reduced by the specific calcium channel blockers verapamil and omega-conotoxin. The efflux of cannabinoid receptor binding activity is greatest within 2 min of stimulation with the Ca++ ionophore A23187. Within this period of time, the cannabinoid receptor binding activity was enhanced by the presence of a cocktail of peptidase inhibitors. Examination of the contribution of individual inhibitors for enhancing high K(+)-released material revealed a selectivity for captopril and thiorphan. The specificity of the released factor for the cannabinoid receptor was corroborated by its ability to compete with the aminoalkylindole radioligand [3H]WIN-55212 for binding to this receptor. Fractions from a semi-purified sample of the effluent demonstrated binding to the cannabinoid receptor and behaved as agonists in that these fractions could inhibit adenylate cyclase activity in neuroblastoma membrane preparations.
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PMID:Endogenous cannabinoid receptor binding activity released from rat brain slices by depolarization. 813 40

Anandamide (arachidonyl ethanolamide) has been identified as an endogenous ligand of cannabinoid receptors on the basis of its ability to displace 3H-labeled synthetic cannabinoid in a binding assay. One well characterized cellular action of cannabinoids is inhibition of hormonally stimulated adenylyl cyclase. Another action of synthetic cannabinoids is potent, stereospecific, and reversible inhibition of N-type calcium currents (ICa) in the NG108-15 neuroblastoma-glioma cell line via a pertussis toxin (PTX)-sensitive pathway, independently of cAMP metabolism. Here we used the N18 neuroblastoma cell line and the whole-cell voltage-clamp technique to show that anandamide also potently inhibits N-type ICa in a PTX-sensitive fashion. As with the cannabinomimetic aminoalkylindole WIN 55,212-2, inhibition by anandamide was voltage dependent and N-ethylmaleimide sensitive. However, anandamide was less efficacious than either WIN 55,212-2 or the nonclassical cannabinoid CP 55,940. Indeed, anandamide appears to act as a partial agonist at the cannabinoid receptor. Application of WIN 55,212-2 always caused further inhibition of ICa in cells exposed to a maximally effective concentration of anandamide, and application of anandamide always caused a partial recovery of ICa in cells exposed to a maximally effective concentration of WIN 55,212-2. This partial agonist property of anandamide suggests that, although anandamide inhibits N-type ICa via a PTX-sensitive G protein, its action as a neuromodulator in the intact animal may be more complex than would be inferred by extrapolating the results of in vivo studies with (-)-delta 9-tetra-hydrocannabinol or synthetic cannabinoids.
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PMID:Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. 837 11

Perforant path synaptic potentials recorded from the outer molecular layer of the dentate gyrus were tested for paired-pulse potentiation and stimulus sensitivity in the presence and absence of the potent cannabinoid receptor ligand, WIN 55,212-2. Extracellular perforant path synaptic potential amplitudes were increased by 51% in 2 mM Ca2+ medium and 60% in 3 mM Ca2+ medium at a conditioning-test (C-T) interval of 10 ms, decreasing to 10-15% facilitation at an 80 ms C-T interval. Exposure to the potent cannabinoid receptor ligand WIN 55,212-2 produced a marked and dose-dependent reduction in the amplitude of the facilitated perforant path synaptic potentials. Maximum paired-pulse facilitation was reduced to 35% and 25% in 2.0 and 5.0 microM WIN 55,212-2 respectively. The effect was selective for potentials facilitated at C-T intervals of 10-60 ms. Input/output (I/O) curves of perforant path field potentials were shifted to the right in a dose-dependent (2.0 and 5.0 microM) manner by WIN 55,212-2. Significant differences in peak amplitudes of perforant path potentials were obtained at all suprathreshold stimulus intensities. A comparison of WIN 55,212-2 (5 microM) with the GABAB receptor agonist baclofen (200 microM) showed that when both drugs were administered independently each produced similar decreases in perforant path paired-pulse potentiation. However when administered together at these concentrations baclofen and WIN failed to potentiate each other, suggesting nonadditivity due to effects on a common process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cannabinoids selectively decrease paired-pulse facilitation of perforant path synaptic potentials in the dentate gyrus in vitro. 854 97

The effect of cannabinoid receptor stimulation on rotational behavior induced by a dopamine D1 and a D2 agonist was studied in rats with unilateral 6-hydroxydopamine-induced lesions of the dopaminergic nigrostriatal pathway. The cannabinoid agonists WIN 55,212-2 (2.5 mg/kg) and CP 55,940 (0.1 mg/kg) both markedly attenuated contralateral rotation induced by the D1 agonist SKF 38393 (1.5 mg/kg). In contrast, WIN 55,212-2 and CP 55,940 did not alter rotation elicited by the D2 agonist quinpirole (0.1 mg/kg). Doses of WIN 55,212-2 and CP 55,940 that attenuated D1-mediated rotation did not produce catalepsy in intact rats or in rats with 6-hydroxydopamine-induced lesions, indicating that the reduction in rotation produced by the cannabinoids was not due to a generalized motor impairment. In addition, the effective dose of WIN 55,212-2, but not CP 55,940, produced only a slight increase in ipsilateral rotation when administered alone, making it improbable that this ipsilateral tendency accounts for the reduction in D1-mediated contralateral rotation. These results suggest a preferential interaction between cannabinoid receptor stimulation and dopamine D1 receptor-mediated behavior.
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PMID:The cannabinoid agonists WIN 55,212-2 and CP 55,940 attenuate rotational behavior induced by a dopamine D1 but not a D2 agonist in rats with unilateral lesions of the nigrostriatal pathway. 859 42


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