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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various water-insoluble cannabinoids as well as SP-111A, the water-soluble derivative of delta 9-tetrahydrocannabinol (delta 9-THC), reduced hCG and dibutyryl-cAMP stimulated testosterone production by rat testicular Leydig cell preparations. With 0.15 microM (0.05 micrograms/ml) 8-beta-OH-delta 9-THC the inhibition was about 50% of stimulated testosterone synthesis. Dose-related inhibitions were apparent with other cannabinoids and their order of potency in inhibiting stimulated steroidogenesis by the interstitial cells in vitro was found to be: 8-beta-OH-delta 9-THC greater than or equal to 11-OH-delta 9-THC greater than CBN = CBD = CBG greater than or equal delta 9-THC = delta 8-THC. The non-stimulated, basal, steroidogenesis was not affected even with 15 microM cannabinoids. The incorporation of L-[U-14C]leucine into the protein of Leydig cells was markedly reduced by 15 microM cannabinoids under both basal and stimulated conditions. The inhibition of steroidogenesis as well as protein synthesis in rat testicular Leydig cell preparations by various cannabinoids cannot be correlated with their psychoactivity. The present data suggest that cannabinoids at very low concentrations may interfere directly in Leydig cells with both protein and testosterone synthesis, and thus with their function.
Mol Cell Endocrinol 1979 Jul
PMID:Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro. 22 40

Extensive behavioral and biochemical characterization of cannabinoid-mediated effects on the central nervous system has revealed at least three lines of evidence supporting the role of a putative guanine nucleotide-binding protein-coupled cannabinoid receptor for cannabimimetic effects, (i) stereoselectivity, (ii) inhibition of the adenylate cyclase/cAMP second messenger system, and (iii) radioligand-binding studies with the synthetic cannabinoid [3H]CP-55,940 indicating a high degree of specific binding to brain tissue preparations. Based on recent findings from our laboratory demonstrating that delta 9-tetrahydrocannabinol markedly inhibited forskolin-stimulated cAMP accumulation in mouse spleen cells, the presence of a guanine nucleotide-binding protein-coupled cannabinoid receptor associated with mouse spleen cells and its functional role in immune modulation were investigated. In the present studies, stereoselective immune modulation was observed with the synthetic bicyclic cannabinoid (-)-CP-55,940 versus (+) CP-56,667 and with 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl, (-)-HU-210 versus (+)-HU-211. In both cases, the (-)-enantiomer demonstrated greater immunoinhibitory potency than the (+)-isomer, as measured by the in vitro sheep red blood cell antibody-forming cell response. Radioligand binding studies produced a saturation isotherm exhibiting approximately 45-65% specific binding to mouse spleen cells. Scatchard analysis demonstrated a single binding site on spleen cells, possessing a Kd of 910 pM and a Bmax of approximately 1000 receptors/spleen cell. RNA polymerase chain reaction of isolated splenic RNA using specific primers for the cannabinoid receptor resulted in the amplification of a 854-kilobase predicted product that hybridized with cannabinoid receptor cDNA, demonstrating the presence of cannabinoid receptor mRNA in mouse spleen. Together, these findings strongly support the role of a cannabinoid receptor in immune modulation by cannabimimetic agents.
Mol Pharmacol 1992 Nov
PMID:Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation. 127 76

The physiologic activity of (-)-delta 9-tetrahydrocannabinol, the most active component of marijuana, and of many synthetic cannabimimetics may be mediated either through receptor binding and functional coupling to specific signal transduction pathways or through nonspecific interaction with cell membrane components. The cloning of the human and rat cannabinoid receptors has provided the opportunity to investigate the binding properties and signal transduction pathways directly associated with these receptors. Cannabinoid receptor cDNA was transfected into and stably expressed in fibroblast cell lines that do not contain native cannabinoid receptors, thus allowing comparison with untransfected cells. Binding constants measured using [3H]CP55,940 indicated that the rat and human cloned cannabinoid receptors were similar to native cannabinoid receptors measured in brain and neural cell lines. The cloned receptors coupled to the inhibition of cAMP accumulation, as previously demonstrated. CP55,940 binding and inhibition of cAMP accumulation were absent in untransfected cells. Cannabinoid agonist-stimulated release of arachidonic acid and increase in intracellular calcium were observed in both transfected and untransfected cells. Stereoselectivity of cannabinoid agonists was demonstrated for binding and functional inhibition of cAMP accumulation, but not for the release of arachidonic acid and intracellular calcium. Therefore, cannabinoid agonists can stimulate signaling pathways through both receptor- and non-receptor-mediated pathways in the same cell.
Mol Pharmacol 1992 Nov
PMID:Cannabinoid agonists stimulate both receptor- and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones. 133 66

Pretreatment of Strongylocentrotus purpuratus sperm with delta 9-tetrahydrocannabinol (THC) prevents the triggering of the acrosome reaction by egg jelly. Examination of THC-treated sperm by transmission electron microscopy reveals that the membrane fusion reaction between the sperm plasma membrane and the acrosomal membrane is completely blocked. Electron-dense deposits are present in the subacrosomal fossa and in the centriolar fossa. The nuclear envelope is fragmented in close proximity to the electron-dense deposits. The electron-dense deposits are not bound by a limiting membrane, stain positively for lipid with thymol and farnesol, and disappear from THC-treated sperm that are extracted with chloroform:methanol (2:1) after glutaraldehyde fixation. The electron-dense deposits are lipid in nature and may be a hydrolytic product of the nuclear envelope. Electron-dense deposits are seen in sperm after 1-10 min treatment with 5-100 microM THC. The electron-dense deposits disappear after removal of THC from the sperm by washing, but the fragmented nuclear envelope in the subacrosomal fossa persists. Cannabidiol (CBD) and cannabinol (CBN) also inhibit the triggering of the acrosome reaction by egg jelly and produce ultrastructural changes in the sperm identical to those elicited by THC. Enhanced phospholipase activity stimulated by THC, CBD, and CBN may be the cause of the accumulation of lipid deposits in the sperm. Metabolites derived from this modification of membrane phospholipids may prevent triggering of the acrosome reaction by egg jelly and thereby inhibit fertilization.
Mol Reprod Dev 1991 May
PMID:Reduction of the fertilizing capacity of sea urchin sperm by cannabinoids derived from marihuana. II. Ultrastructural changes associated with inhibition of the acrosome reaction. 164 73

We reported earlier that delta 9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marihuana, increased markedly the level of unesterified arachidonic acid (AA) in guinea pig cerebral cortex slices prelabeled with [14C]AA. The purpose of the present study was to clarify the mechanism underlying THC-enhanced mobilization of AA. We could find little data to support an involvement for phospholipase A2 in this response. For example, the levels of lysophosphatidylcholine or lysophosphatidylethanolamine were not elevated after incubation with THC. A role for phosphoinositidase C-initiated lipolytic pathways was excluded, because neither basal nor acetylcholine-stimulated inositol phosphate formation was altered by THC. When we prelabeled slices with [14C]stearate or [3H]glycerol, THC did not elevate levels of unesterified [14C]stearate, nor did we observe significant changes in the phospholipids that were labeled with either precursor. These findings were in marked contrast to the previously reported reductions in [14C]AA-labeled phosphatidylinositol after exposure of prelabeled brain slices to THC; moreover, they suggested that the THC-induced effects on brain lipid metabolism in vitro were rather specific for AA. We show here that, when the acylation of brain lipids with AA was measured by addition of [3H]AA in the presence and absence of THC at zero time and incubation for 1 hr at 37 degrees, THC elicited marked, dose-dependent, and saturable reductions in esterified [3H]AA levels. The reductions in incorporation were balanced by increases in unesterified [3H]AA. The IC50 for the effect was on the order of 8 microM, and a maximal response occurred at 32 microM. We observed that the THC-induced suppression in acylation of the phospholipids by radiolabeled AA was up to 5-fold greater than the THC-elicited loss of AA from slices prelabeled before exposure to THC. The largest inhibitions of acylation were in phosphatidylinositol; the suppression of radioactivity in this phospholipid accounted for over 50% of the rise in unesterified [3H]AA. The radioactivity incorporated in triacylglycerols were also reduced markedly by THC. In contrast, the incorporation of radioactivity in phosphatidylcholine remained unaffected by THC. Taken together, these findings suggest that THC mobilizes AA by inhibiting acylation of certain lipids with AA, particularly phosphatidylinositol and triacylglycerol, rather than by liberating fatty acids by lipolysis. Comparison of the effects of several primary cannabinoids on lipid acylation with [3H]AA revealed that there was no relationship between the potencies of cannabinoids in inhibiting the incorporation of [3H]AA into membrane lipids and their psychoactive potencies in vivo; moreover, the stereoisomers of THC were equipotent.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1991 Oct
PMID:Delta 9-tetrahydrocannabinol inhibits arachidonic acid acylation of phospholipids and triacylglycerols in guinea pig cerebral cortex slices. 165 90

Structure-activity relationship studies have suggested that the phenolic hydroxyl group is essential for the pharmacological activity of the cannabinoids. However, it remains to be established whether it is the hydrogen of the phenolic hydroxyl that is important (possibly because this hydrogen can participate in a hydrogen bonding interaction) or whether it is the oxygen of the phenolic hydroxyl that is important (possibly because one of the lone pairs of electrons in this oxygen can serve as a hydrogen bond acceptor). Two new etherified cannabinoids were prepared in which the phenolic hydroxyl oxygen is incorporated into a fourth ring. These new compounds were designed to test the importance both of the phenolic hydroxyl oxygen and of the orientation of its lone pairs of electrons for cannabinoid pharmacological activity. O,2-Propano-delta 8-tetrahydrocannabinol (0,2-Propano-delta 8-THC) was designed to mimic delta 9-THC in its phenol conformation I (C2-C1-O-H = 7 degrees). O,10-Methano-delta 9-tetrahydro-cannabinol (0,10-Methano-delta 9-THC) was designed to mimic delta 9-THC in its phenol conformation II (C2-C1-O-H = 167 degrees). Molecular mechanics calculations revealed that 1) there are two accessible minimum energy conformers for O,2-propano-delta 8-THC, which differ principally in the conformation of the new fourth ring, and 2) there are three accessible minimum energy conformers for O,10-methano-delta 9-THC, the first two of which differ mainly in the conformation of the new fourth ring, whereas the third possesses an alternate pyran ring conformation. Wave functions and molecular electrostatic potential (MEP) maps were calculated for each accessible conformer of O,2-propano-delta 8-THC and of O,10-methano-delta 9-THC. The resultant MEP maps compared well with the corresponding MEP maps generated for delta 9-THC in each of its two minimum energy conformations (two phenolic hydroxyl positions). These results imply that 1) O,2-propano-delta 8-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation 1 and 2) O,10-methano-delta 9-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation II. Pharmacological evaluation of the analogs revealed that O,10-methano-delta 9-THC was inactive in all mouse tests, as well as the rat drug discrimination model. O,2-Propano-delta 8-THC was similar to delta 8-THC in that it depressed rectal temperature and produced antinociception and ring immobility in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Pharmacol 1990 Dec
PMID:Investigation of the role of the phenolic hydroxyl in cannabinoid activity. 217 6

We have previously shown that addition of exogenous arachidonic acid to pancreatic acinar cells inhibits the incorporation of myo-[3H]inositol into membrane phosphoinositides and causes a reduction in the steady state levels of [32P]phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2). In the present study, delta-9-tetrahydrocannabinol (THC) was utilized to raise endogenous levels of arachidonic acid. In acinar cells simultaneously prelabeled with [3H]arachidonic acid and [32P]Pi, THC (1-20 microM) produced a concentration-dependent increase in free [3H]arachidonic acid release and a reduction in the steady state levels of [32P]Ptd-Ins4,5P2. THC (1-20 microM) also caused a concentration-dependent inhibition of myo-[3H]inositol trisphosphate accumulation, cytoplasmic Ca2+ level, and amylase secretion elicited by 0.1 microM caerulein. The findings that THC (20 microM) was unable to inhibit either the rise in [Ca2+]i elicited by ionomycin, or the secretory response to phorbol myristic acid or ionomycin, indicate that THC exerts a selective inhibitory effect on the phosphoinositide messenger system. These results support the postulate that endogenous arachidonic acid serves as a negative feedback regulator of phosphoinositide turnover in exocrine pancreas.
Mol Pharmacol 1988 Oct
PMID:Relationship between delta-9-tetrahydrocannabinol-induced arachidonic acid release and secretagogue-evoked phosphoinositide breakdown and Ca2+ mobilization of exocrine pancreas. 245 92

The conformation for each of two cannabinoids, delta 9-tetrahydrocannabinol (THC), the principal active constituent of marihuana, and delta 9,11-THC, a biologically inactive structural isomer of delta 9- THC, is analyzed by interpreting 1H-1H and 13C-1H coupling constants and nuclear Overhauser effects determined using one-and two-dimensional 1H and 13C NMR techniques. The interpretation of both vicinal and long range coupling constants was necessary to deduce the conformations of these tricyclic molecules with certainty, with nuclear Overhauser effect enhancements used, when appropriate, to confirm the results. These findings provide insights into the structure-activity requirements for the cannabinoids.
Mol Pharmacol 1989 Apr
PMID:The conformational analysis of delta 9- and delta 9,11-tetrahydrocannabinols in solution using high resolution nuclear magnetic resonance spectroscopy. 253 57

The abilities of lipophilic cannabinoid drugs to regulate adenylate cyclase activity in neuroblastoma cell membranes were analyzed by thermodynamic studies. Arrhenius plots of hormone-stimulated adenylate cyclase activity exhibited a break point at 20 degrees. The break point was reduced to 14 degrees by benzyl alcohol, consistent with results from other laboratories that have correlated this response with the increase in membrane fluidity induced by benzyl alcohol. Because cannabinoid drugs partition into membrane lipids and alter membrane fluidity parameters in a number of model systems, it was of interest to examine the influence of delta 9-tetrahydrocannabinol and cannabidiol on enzyme activity analyzed by the Arrhenius plot. delta 9-Tetrahydrocannabinol, known to inhibit adenylate cyclase, failed to decrease the transition temperature either at 1 microM or at concentrations exceeding its aqueous solubility (30 microM), suggesting that delta 9-tetrahydrocannabinol could not mimic the effects observed with benzyl alcohol. In contrast, 30 microM cannabidiol, which stimulated enzyme activity slightly, decreased the Arrhenius plot break point to 17.5 degrees. The decrease in the transition temperature in response to benzyl alcohol or cannabidiol was not accompanied by a change in activation energies above or below the transition temperature. delta 9-Tetrahydrocannabinol inhibits adenylate cyclase activity via Gi as does the muscarinic agonist carbachol (Howlett et al., Mol Pharmacol 29: 307-313, 1986). Both carbachol and delta 9-tetrahydrocannabinol decreased the enthalpy and entropy of activation. The net free energy of activation at 37 degrees was increased in the presence of both of these inhibitory agonists. These data suggest that, for the entropy-driven hormone-stimulated adenylate cyclase enzyme, less disorder of the system occurs in the presence of regulators that inhibit the enzyme via Gi. In summary, thermodynamic data suggest that cannabidiol can influence adenylate cyclase by increasing membrane fluidity, but that the inhibition of adenylate cyclase by delta 9-tetrahydrocannabinol is not related to membrane fluidization.
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PMID:Regulation of adenylate cyclase by cannabinoid drugs. Insights based on thermodynamic studies. 255 20

In order to investigate the effects of cannabinoids on prostaglandin (PG) formation in the mammalian central nervous system, slices were prepared from different regions of guinea pig brain and incubated with (-)-trans-delta 9-tetrahydrocannabinol (THC) with or without acetylcholine (ACh). The amounts of prostaglandins E (PGE) and (F (PGF) released into the medium were measured by radioimmunoassay. Incubation of cerebral cortex slices for 1 hr with concentrations of THC over the range of 0.8-16 microM significantly inhibited the formation of both PGE and PGF by up to 50% of control levels. Incubation of cortical slices with delta 8-THC, a psychoactive THC congener, resulted in similar dose-dependent inhibitions in both PGE and PGF levels. Congeners of THC devoid of psychoactivity, namely, cannabidiol and the inactive stereoisomer of THC, were less potent inhibitors of PGE synthesis. In marked contrast to the inhibitory effect of the psychoactive cannabinoids, PGF levels were elevated in the presence of the nonpsychoactive congeners. The effects of THC on PG formation were compared in different brain regions. In striatal slices, 0.8 microM THC significantly stimulated PG formation but did not affect PG levels in the cerebellum. In order to gain insight into the interaction between THC and endogenous neurotransmitters, we compared the effect of THC on the ACh-induced increase in PG formation in the cerebral cortex and the cerebellar cortex. In the cerebral cortex, 0.8 microM THC abolished the ACh-induced increase in PGE levels and inhibited the rise in PGF by 70%. In contrast, THC did not significantly affect the ACh-induced rise in PG levels in the cerebellum. The results indicate that cannabinoids alter both the basal and ACh-enhanced formation of PGE and PGF in the brain and that these effects are structurally and regionally specific.
Mol Pharmacol 1987 Nov
PMID:Effects of delta 9-tetrahydrocannabinol on prostaglandin formation in brain. 282 83


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