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

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-containing benzofuran ring; the second pair [(+)-HU-253 and (-)-HU-254] does not have an oxygen-containing ring. The onset of cannabimimetic activity was slower, and duration of action was longer for the test compounds than for THC. HU-250 exhibited cannabimimetic activity with a potency similar to THC in both species; HU-249 was 22 times less active than THC. The pattern of response rate and THC-like responding obtained with HU-249 were dissociated; THC-like responding occurred during the later test intervals when suppression of response rate was reduced. HU-250 bound to the cannabinoid receptor with a Ki of 47.6 nM, essentially identical to that of THC. HU-249 was much less active, with a Ki of 28.3 microM. The triacetate enantiomers, HU-253 and HU-254, occasioned THC-like responding in both species, HU-254 being about 4.5 times less potent than THC and 3 to 4 times more potent than HU-253. In binding, HU-253 was also less potent than HU-254. The corresponding triols were considerably more potent than the acetates; (-)-HU-256 had a Ki of 198 nM, whereas (+)-HU-255 had a Ki of 43.8 nM, comparable to that of THC.
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PMID:Discriminative stimulus effects and receptor binding of enantiomeric pairs of cannabinoids in rats and pigeons; a comparison. 838 75

In this paper, it is hypothesized that the distinction between certain active and inactive cannabinoids is that the inactive analogs possess extra volume associated with their carbocyclic rings that may be responsible for an unfavorable interaction at the cannabinoid receptor. Using the active analog approach, a model is developed of a region of steric interference at this receptor using the active cannabinoids (-)-trans-delta 9-tetrahydrocannabinol, (-)-trans-delta 8-tetrahydrocannabinol, (-)-11-hydroxy-beta-hexahydrocannabinol, and a (-)-trans-11-hydroxy-delta 8-tetrahydrocannabinol dimethylheptyl derivative and the inactive cannabinoids (9S,6aR)-trans-delta 10,10a-tetrahydrocannabinol and a (+)-trans-11-hydroxy-delta 8-tetrahydrocannabinol dimethylheptyl derivative. Each of these molecules satisfy the cannabinoid pharmacophoric requirements, i.e., a phenolic oxygen at C1 and a side chain of acceptable length at C3. Accessible conformers of each molecule were identified by using the method of molecular mechanics as encoded in the MMP2(85) program. The MAP facility within the Chem-X molecular modeling program was then used to calculate the region of steric interference (termed the receptor essential volume, REV) from these accessible conformers. The calculations revealed an REV region located near the top of the carbocyclic ring in the bottom face of the molecule. In order to explore the use of this REV to account for the activities of other cannabinoids, the minimally active classical cannabinoid (-)-11-hydroxy-alpha-hexahydrocannabinol, an active benzofuran cannabinoid, and the active nonclassical cannabinoid CP-47,497 were then studied. In each case, the activity or minimal activity of each compound can be explained on the basis of the ability of one or more accessible conformer of each molecule to clear the REV calculated here. The results of this study provide an explanation at the molecular level for observed activity differences between cannabinoids that exhibit shape differences associated with their carbocyclic rings.
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PMID:Characterization of a region of steric interference at the cannabinoid receptor using the active analog approach. 851 Jan 4

Anandamides are endogenous fatty acid ethanolamides that have been shown to bind to the cannabinoid receptor and possess cannabimimetic activity yet are structurally dissimilar from the classical cannabinoids found in Cannabis sativa. We have employed molecular dynamics studies of a variety of anandamides to characterize their conformational mobility and determine whether there are pharmacophoric similarities with delta 9-THC. We have found that a looped conformation of these arachidonyl compounds is energetically favorable and that a structural correlation between this low-energy conformation and the classical cannabinoids can be obtained with the superposition of (1) the oxygen of the carboxyamide with the pyran oxygen in delta 9-THC, (2) the hydroxyl group of the ethanol with the phenolic hydroxyl group of delta 9-THC, (3) the five terminal carbons and the pentyl side chain of delta9-THC, and (4) the polyolefin loop overlaying with the cannabinoid tricyclic ring. The shape similarity is extended to show that other fatty acid ethanolamides that possess varying degrees of unsaturation also vary in their conformational mobility, which affects their ability to overlay with delta 9-THC as described above. Within this series of compounds, the most potent analog, the tetraene (arachidonyl) analog (i.e., anandamide itself), was determined to have restricted conformational mobility that favored an optimal pharmacophore overlay with delta9-THC. Eight pharmacologically active anandamide analogs are shown to have similar conformational mobility and pharmacophore alignments that are conformationally accessible. Furthermore, when these compounds are aligned to delta 9-THC according to the proposed pharmacophore overlay, their potencies are predicted by a quantitative model of cannabinoid structure--activity relationships based solely on classical and nonclassical cannabinoids with a reasonable degree of accuracy. The ability to incorporate the pharmacological potency of these anandamides into the cannabinoid pharmacophore model is also shown to support the relevance of the proposed pharmacophore model.
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PMID:Structure-activity analysis of anandamide analogs: relationship to a cannabinoid pharmacophore. 855 15

The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-delta 8-tetrahydrocannabinol (O,2-propano-delta 8-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-delta 8-THC, O,2-propano delta 9,11-THC, O,2-propano-9-oxo-11-nor-hexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propano-9 alpha- and O,2-propano-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, Ki(CB1) = 90 nM, Ki(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, Ki(CB1) = 26 nM, Ki(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-delta 9,11-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities in the O,2-propano analogs may be due to differences in solvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be a results of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.
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PMID:Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: synthesis and characterization of a series of O,2-propano-delta 8-tetrahydrocannabinol analogs. 937 52

Constrained molecular dynamics simulations on anandamide, together with a systematic distance comparison search, have revealed a specific low-energy conformer whose spatial disposition of the pharmacophoric elements closely matches that of HHC. This conformer enables near superposition of the following: (1) the oxygen of the carboxyamide and the phenolic hydroxyl group of HHC, (2) the hydroxyl group of the ethanol and the cyclohexyl hydroxyl group of HHC, (3) the alkyl tail and the lipophilic side chain of HHC, and (4) the polyolefin loop and the tricyclic ring structure of HHC. The close matching of common pharmacophoric elements of anandamide with HHC offers persuasive evidence of the biological relevance of this conformer. The proposed pharmacophore model was capable of discriminating between structurally related compounds exhibiting different pharmacological potency for the CB1 cannabinoid receptor, i.e., anandamide and N-(2-hydroxyethyl)prostaglandinamide. Furthermore, a 3D-QSAR model was derived using CoMFA for a training set of 29 classical and nonclassical analogues which rationalized the binding affinity in terms of steric and electrostatic properties and, more importantly, which predicted the potency of anandamide in excellent agreement with experimental data. The ABC tricyclic HU-210/HU-211 and ACD tricyclic CP55,243/CP55,244 enantiomeric pairs were employed as test compounds to validate the present CoMFA model. For each enantiomeric pair, the CoMFA-predicted log Ki values correctly identified that enantiomer exhibiting the higher affinity for the receptor.
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PMID:Derivation of a pharmacophore model for anandamide using constrained conformational searching and comparative molecular field analysis. 978 95

In order to make further structural comparisons between tetrahydrocannabinol and anandamide, substituents at C1 and C3 of the phenolic ring of tetrahydrocannnabinol were altered. In order to examine the alignment of the phenolic hydroxyl of tetrahydrocannnabinol with the hydroxyl group of anandamide, 1-fluoro-1-deoxy-tetrahydrocannnabinol analogs were prepared. These analogs had low affinity for the CB(1) cannabinoid receptor and were considerably less potent than tetrahydrocannnabinol in producing pharmacological effects in mice. These results suggest that these two oxygen moieties do not overlap. Additionally, the fact that a fluorine group can only accept hydrogen bonds suggest that the phenolic oxygen at the C1 position of tetrahydrocannnabinol donates electrons for hydrogen bonding rather than the hydrogen of the hydroxyl group interacting with the receptor. Additionally, substitution of a fluorine for the hydroxyl group at C1 led to analogs with higher affinity for CB(2) than CB(1) cannabinoid receptors, thereby underscoring a fundamental difference in the binding properties of these two receptor subtypes.
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PMID:Assessment of structural commonality between tetrahydrocannabinol and anandamide. 1179 Mar 76

Cannabinoids are known to downregulate immune response but the role for cannabinoid receptors in cannabinoid-induced immunosuppression is still unclear. To address this question, the interference of CB1 and CB2 receptor antagonists with the inhibition of TNF-alpha production by synthetic cannabinoid WIN 55,212-2 was studied using human peripheral blood mononuclear cells (PBMC) in vitro. CB2 (SR 144528) but not CB1 (SR 141716A) receptor antagonist dose dependently interfered with WIN 55,212-2-induced inhibition of TNF-alpha synthesis. Also, WIN 55,212-2 decreased fMLP-induced reactive oxygen species generation in lipopolysaccharide (LPS)-primed PBMC. However, the high concentrations of cannabinoid receptor ligands needed to achieve significant effects suggest that the observed effects may be in part cannabinoid receptor independent.
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PMID:Effect of the cannabinoid receptor ligand, WIN 55,212-2, on superoxide anion and TNF-alpha production by human mononuclear cells. 1196 32

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
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PMID:Therapeutic potential of cannabinoids in CNS disease. 1261 97

A set of 30 substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB(1) cannabinoid receptor has been evaluated. These compounds are derived from the previously described cannabinoid ligands 5,5'-diphenylimidazolidine-2,4-dione (hydantoins). The replacement of the oxygen by a sulfur leads to an increase of the affinity while the function-i.e., inverse agonism-determined by [(35)S]GTPgammaS experiments remains unaffected. Finally, to evaluate the molecular parameters that could influence the affinity of the thiohydantoins, molecular electrostatic potential as well as lipophilicity calculations were undertaken on representative thiohydantoins and hydantoins derivatives. In conclusion, 5,5'-bis-(4-iodophenyl)-3-butyl-2-thioxoimidazolidin-4-one (31) and 3-allyl-5,5'-bis(4-bromophenyl)-2-thioxoimidazolidin-4-one (32) possess the highest affinity for the CB(1) cannabinoid receptor described to date for the hydantoin and thiohydantoins series when compared in a same bioassay.
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PMID:Substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one as CB1 cannabinoid receptor ligands: synthesis and pharmacological evaluation. 1580 40

Anandamide (arachidonyl-ethanolamide, AEA) is an important endogenous cannabinoid ligand isolated from porcine brain. AEA has a flexible molecular structure with a series of four non-conjugated double bonds, a hydrophobic alkyl chain, and a carboxyamide head group. It is known that AEA binds to cannabinoid receptor and induces cannabimimetic activity. However, questions still remain about the three-dimensional arrangement of the pharmacophoric groups of AEA that facilitate its interaction with cannabinoid receptor, a member of transmembrane G-protein coupled receptors (GPCRs). Such information is of critical importance for the design of novel analogs of potential therapeutic values. In the present studies, we developed a combined approach of 2D high-resolution NMR and computer modeling to investigate conformational features of AEA in solution. The developed method and experimental data is then applied to study the structural properties of AEA in a membrane-like environment that will be reported elsewhere. In addition to the measured NOEs, the dihedral angle constraints were for the first time being used as experimentally-determined structural constraints for performing molecular dynamics simulations to refine the NMR-determined AEA conformations. Our results showed that AEA prefers an extended pseudo-helical conformation in solution with two oxygen atoms pointing towards the same side and a straight pentyl chain, which was an averaged conformation observed on the basis of NMR time scale. The results were correlated to the computer predicted AEA models reported by others. The established NMR-based computational approach provides an alternative way to explore further the detailed conformational properties of AEA that encodes important pharmacophoric and conformational information regarding the activation of cannabinoid receptors.
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PMID:Preferred conformations of endogenous cannabinoid ligand anandamide. 1582 73


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