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

The 1,1-dimethylheptyl (DMH) homologue of 7-hydroxy-delta 6-tetrahydrocannabinol (3) is the most potent cannabimimetic substance reported so far. Hydrogenation of 3 leads to a mixture of the epimers of 5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol or to either the equatorial (7) or to the axial epimer (8), depending on the catalysts and conditions used. Compound 7 discriminates for delta 1-THC (2) in pigeons (ED50 = 0.002 mg/kg, after 4.5 h), at the potency level of 3, and binds to the cannabinoid receptor with a KD of 45 pM, considerably lower than the Ki of 180 pM measured for compound 3 and the Ki of 2.0 nM measured for CP-55940 (1), a widely employed ligand. Tritiated 7 was used as a novel probe for the cannabinoid receptor.
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PMID:A novel probe for the cannabinoid receptor. 131 25

-(-)-5'-Bromo-delta 8-THC, (-)-5'-trifluoromethyl-delta 8-THC, (-)-5'-iodo-delta 8-THC, (-)-5'-fluoro-delta 8-THC, (-)-11-fluoro-delta 8-THC and (-)-2-iodo-delta 8-THC were synthesized and evaluated in male ICR mice for their effects on sedation, temperature, catalepsy and antinociception following intravenous injection. The analogs were also tested for relative affinities for cannabinoid binding sites derived from rat cortex membranes, using [3H] CP-55,940 as the tritiated ligand. The results showed that the 5'-bromo, 5'-iodo and 5'-trifluoromethyl analogs were 2-40 times more potent than (-)-delta 8-THC in all biological tests, while the 5'-fluoro and 11-fluoro derivatives were less active. With the 2-iodo analog, a 12-fold separation was observed between antinociception and sedation, pointing to the importance of the side chain orientation in determining cannabinoid activity and to the possible involvement of more than one cannabinoid receptor site. The pharmacological data closely paralleled the data obtained from the binding assay.
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PMID:Pharmacological evaluation of halogenated delta 8-THC analogs. 166 15

The present overview covers various aspects of research going on in the Cannabis field in the Department of Natural Products at the Hebrew University. In the first part we discuss, and try to explain, the reason for the absence of the term Cannabis (and possibly also opium) in the Old Testament. In the second part we bring evidence that, contrary to widely held views, stereospecificity of cannabinoid action is extremely high, and in certain cases almost absolute. Previous results seem to have been due to impurities in the samples tested. (+)-Delta-1-THC, (+)-delta-6-THC and (+)-7-hydroxy-delta-6-THC, when purified sufficiently, exhibit activity of about 1% of that of the natural (-) enantiomers. A new labelled cannabinoid ligand has been prepared by catalytic reduction of (-)-7-hydroxy-delta-6-THC dimethylheptyl. The equatorial C-1 epimer obtained binds to the cannabinoid receptor with a KI of 40 pM. This compound is one of the most active cannabinoids tested so far for binding to the canabinoid receptor, and may become an important tool in cannabinoid research.
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PMID:A random walk through a cannabis field. 180 38

The recent preparation of the enantiomers of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (THC-DMH), recrystallized to absolute enantiomeric purity, has made it possible to examine the requirement for stereospecificity for the interaction of this component with the cannabinoid receptor, defined by the binding of [3H]CP-55,940 and the adenylate cyclase enzyme. The enantiomer (-)11-OH-delta 8-THC-DMH exhibited a fully efficacious and potent (IC50 = 1.8 nM) inhibition of the accumulation of cAMP in intact N18TG2 cells. The (-)enantiomer was as efficacious and potent (Kinh = 7.2 nM) as desacetyllevonantradol in inhibiting adenylate cyclase activity in membrane preparations. The (-)enantiomer was able to compete fully for the specific binding of [3H]CP-55,940 to membranes from the brain of the rat in homologous displacement studies (Ki = 234 pM). The potency ratios exhibited by the (-) to (+)enantiomers of 11-OH-delta 8-THC-DMH exceeded 1000 for each of these activities.
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PMID:Stereochemical effects of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. 215 35

Using a reverse transcription-coupled PCR, we demonstrated that both brain and spleen type cannabinoid receptor (CB1-R and CB2-R, respectively) mRNAs are expressed in the preimplantation mouse embryo. The CB1-R mRNA expression was coincident with the activation of the embryonic genome late in the two-cell stage, whereas the CB2-R mRNA was present from the one-cell through the blastocyst stages. The major psychoactive component of marijuana (-)-delta-9-tetrahydrocannabinol [(-)-THC] inhibited forskolin-stimulated cAMP generation in the blastocyst, and this inhibition was prevented by pertussis toxin. However, the inactive cannabinoid cannabidiol (CBD) failed to influence this response. These results suggest that cannabinoid receptors in the embryo are coupled to inhibitory guanine nucleotide binding proteins. Further, the oviduct and uterus exhibited the enzymatic capacity to synthesize the putative endogenous cannabinoid ligand arachidonylethanolamide (anandamide). Synthetic and natural cannabinoid agonists [WIN 55,212-2, CP 55,940, (-)-THC, and anandamide], but not CBD or arachidonic acid, arrested the development of two-cell embryos primarily between the four-cell and eight-cell stages in vitro in a dose-dependent manner. Anandamide also interfered with the development of eight-cell embryos to blastocysts in culture. The autoradiographic studies readily detected binding of [3H]anandamide in embryos at all stages of development. Positive signals were present in one-cell embryos and all blastomeres of two-cell through four-cell embryos. However, most of the binding sites in eight-cell embryos and morulae were present in the outer cells. In the blastocyst, these signals were primarily localized in the mural trophectoderm with low levels of signals in the polar trophectoderm, while little or no signals were noted in inner cell mass cells. These results establish that the preimplantation mouse embryo is a target for cannabinoid ligands. Consequently, many of the adverse effects of cannabinoids observed during pregnancy could be mediated via these cannabinoid receptors. Although the physiological significance of the cannabinoid ligand-receptor signaling in normal preimplantation embryo development is not yet clear, the regulation of embryonic cAMP and/or Ca2+ levels via this signaling pathway may be important for normal embryonic development and/or implantation.
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PMID:The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. 756 54

In order to explore the structural requirements for cannabinoid activity we have been involved in the design and synthesis of stereochemically defined high affinity probes for the cannabinoid receptor. This effort has involved the development of irreversible ligands which will allow us to obtain detailed information on the cannabinoid receptor active site(s). The irreversible ligands, which incorporate highly reactive functional groups in a strategic position of the ligand, may form covalent bonds with amino acid residues at the receptor active site or in the neighborhood of this site. We shall discuss the biochemical properties of one of these probes, which incorporates the electrophilic isothiocyanate group into the structure of the highly potent cannabinoid agonist (-)-1',1'-dimethylheptyl-delta 8-THC. This ligand, (-)-7'-isothiocyanato-1',1'-dimethylheptyl-delta 8-THC (7'-NCS-DMH-delta 8-THC), was evaluated for its affinity for cannabinoid binding sites using rat forebrain membrane preparations and found to have an apparent IC50 value of 660 pM. Incubation of the membrane preparation with a ligand concentration of five times the apparent IC50 resulted in the irreversible occupation of nearly all of the receptor specific binding sites.
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PMID:A novel electrophilic high affinity irreversible probe for the cannabinoid receptor. 777 19

The effect of delta 8-THC on experimental autoimmune encephalomyelitis (EAE) was examined. delta 8-THC is an analogue of delta 9-THC, the psychoactive component of marijuana. It is more stable and less psychotropic than delta 9-THC and like the latter it binds to the brain cannabinoid receptor. Two strains of rats were inoculated for EAE, and delta 8-THC (40 mg/kg) was administered for up to 21 days. delta 8-THC significantly reduced the incidence and severity of neurological deficit in both rat strains. The beneficial influence of delta 8-THC only occurred on oral administration and not with parenteral injection. Serum corticosterone levels were twofold elevated in rats with EAE chronically treated with delta 8-THC. These results suggest that suppression of EAE by cannabinoids may be related to their effect on corticosterone secretion.
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PMID:Suppression of experimental autoimmune encephalomyelitis by cannabinoids. 785 52

It has been shown previously that the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide 20:4, n-6) induces in vivo and in vivo effects typical of a cannabinoid partial agonist. We now report that the synthetic docosahexaenylethanolamide (anandamide 22:6, n-3) shows similar activities. In addition we show that these two anandamides, under certain experimental conditions, antagonize the effects of delta 9-THC both in vivo and in vitro. Thus a significant decrease in the potency of delta 9-THC-induced inhibition of adenylate cyclase was observed in N18TG2 neuroblastoma cells that were pretreated with low concentrations of anandamides. At these low concentrations of anandamides had no effect when applied alone. In vivo, Sabra or ICR mice were subjected to a tetrad of tests, designed to detect cannabinoid-induced effects. Mice pretreated (i.p.) with 10 mg/kg of delta 9-THC received injections with anandamides. Only low doses (0.0001-0.1 mg/kg) of the anandamides, which had no effects when administered alone, partially or fully inhibited the THC-induced effects. These findings suggest that the inhibition of delta 9-THC-induced effects by low doses of anandamides may be due to partial agonistic effects of these materials. It is possible that low doses of the anandamides are capable of activating a Gs protein mediated signaling pathway, or may cause an allosteric modulation of the cannabinoid receptor.
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PMID:Low doses of anandamides inhibit pharmacological effects of delta 9-tetrahydrocannabinol. 785 84

Anandamide (arachidonylethanolamide), an arachidonic acid derivative isolated from the porcine brain, displays binding characteristics indicative of an endogenous ligand for the cannabinoid receptor. The functional activity of anandamide was tested in vivo using behavioral and physiological paradigms in laboratory rodents. At IP doses from 2 to 20 mg/kg in mice, anandamide significantly decreased spontaneous motor activity in a Digiscan open field. Rectal body temperature significantly decreased at doses of 10 and 20 mg/kg in rats. At doses from 0.03 to 30 mg/kg, anandamide had no significant effect on chow consumption in ad lib fed rats. Over the dose range of 2-20 mg/kg, anandamide did not show anxiolytic properties in the mouse light<-->dark exploration model of anxiety. Over the dose range of 0.3-3 mg/kg, anandamide had no effect on choice accuracy or session duration in the delayed nonmatching to sample memory task (DNMTS) in rats. These results demonstrate that anandamide has biological and behavioral effects in awake rodents, some of which are similar to the reported actions of THC.
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PMID:Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. 790 42

This study examined the immunoregulatory effects of anadamide, the recently identified first endogenous cannabinoid receptor ligand. Anadamide caused dose-dependent inhibition of mitogen-induced T and B lymphocyte proliferation. Its potency was 3- and 10-fold less than that of the synthetic cannabinoids delta 8-tetrahydrocannabinol (delta 8-THC) and CP55940, respectively. Anadamide effects on DNA synthesis in T and B lymphocytes occurred rapidly as exposure of the cells during the final 4 h of culture was sufficient to achieve > 40% inhibition. Low doses of anadamide which caused significant inhibition of lymphocyte proliferation caused DNA fragmentation as demonstrated by immunohistochemistry, FACS analysis and Southern blotting. Apoptosis was also induced by high concentrations of delta 8-THC, but not by CP55940. Brain and peripheral cannabinoid receptor mRNA was expressed in PBMC with varying levels between individual donors. In summary, these findings demonstrate immunosuppressive effects of anadamide which are associated with inhibition of lymphocyte proliferation and the induction of cell death by apoptosis.
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PMID:Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. 796 80


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