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PubMed1997

Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system.

Cannabinoid receptor (CB) expression was characterized in immunological cell and tissue preparations. Northern analysis revealed approximately 6-kb transcripts for CB1 (brain-type) in mouse spleen and brain and in rat cerebellum. CB1 was not detected in mouse thymus or rat spleen RNA by Northern analysis. CB2 (peripheral) was detected as a approximately 4-kb transcript in mouse spleen and thymus and as approximately 2.4-kb transcripts in rat spleen. Quantitation of CB2 transcripts in mouse spleen and thymus revealed approximately 4 x 10(3) and approximately 4 x 10(2) molecules/100 ng RNA, respectively, with no quantifiable CB2 in mouse brain. Conversely, CB1 was expressed in mouse brain (approximately 2 x 10(5) molecules/100 ng RNA) with lower expression in mouse spleen (approximately 2 x 10(2) molecules/100 ng RNA) and was not quantifiable in mouse thymus. Competition binding in intact mouse splenocytes demonstrated that nonradiolabeled cannabinoids CP-55940, Win-55212-2, CP-56667, delta 9-THC, and cannabinol all competed for receptor binding with 3H-CP-55940, a high-affinity nondiscriminating CB1 and CB2 receptor ligand. Based on previous findings which demonstrated a marked inhibition of T-cell-dependent immune responses by cannabinoids, primary T cells and several T-cell lines were characterized. Radioligand binding analysis identified 100-300 cannabinoid receptor binding sites/cell with an approximate Kd of 200-700 pM in purified splenic T cells which also exhibited cannabinoid-induced inhibition of adenylate cyclase. Northern analysis of human T-cell lines revealed approximately 2.4-kb CB2 mRNA transcripts but no CB1 in HPB-ALL cells, a cell line which also exhibited inhibition of adenylate cyclase by delta 9-THC. Conversely, Jurkat E6-1 cells expressed an unusual mRNA banding pattern for CB2 expressing three distinct transcript sizes, none of which were 2.4 kb, the size for human CB2. Jurkat also did not express CB1 mRNA and did not exhibit inhibition of adenylate cyclase when treated with delta 9-THC. Collectively, these results provide further evidence that CB2 is the predominant cannabinoid receptor within the immune system and that this form of the receptor is expressed on T cells.

Adenylyl Cyclases↗

PubMed2005

A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833.

Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.

Analgesics↗

PubMed1996

Determination of the cannabinoid receptors in mouse x rat hybridoma NG108-15 cells and rat GH4C1 cells.

The cannabinoid receptors expressed in the mouse neuroblastoma X rat glioma NG108-15 cell and the rat pituitary tumor GH4C1 cell were determined by polymerase chain reaction, dideoxysequencing and pharmacologically. The CB1 but not the CB2 or CB1A cannabinoid receptor was found in both cell lines. The cDNA identified in GH4C1 cells corresponds to the rat CB1 receptor. Interestingly, NG108-15 cells express two distinct cDNAs, one corresponds to the rat and the other to the mouse CB1 receptor. The newly developed CB1 receptor selective antagonist SR141716A was found to reverse cannabinoid agonist (WIN55212-2 or CP55940)-induced adenylyl cyclase inhibition. These results provide more direct evidence that the CB1 receptor is mediating the pharmacological actions of cannabinoids in NG108-15 and GH4C1 cells.

Amino Acid Sequence↗

PubMed1996

Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat.

Anandamide (arachidonylethanolamide) is a novel lipid neurotransmitter first isolated from porcine brain which has been shown to be a functional agonist for the cannabinoid CB1 and CB2 receptors. Anandamide has never been isolated from human brain or peripheral tissues and its role in human physiology has not been examined. Anandamide was measured by LC/MS/MS and was found in human and rat hippocampus (and human parahippocampal cortex), striatum, and cerebellum, brain areas known to express high levels of CB1 cannabinoid receptors. Significant levels of anandamide were also found in the thalamus which expresses low levels of CB1 receptors. Anandamide was also found in human and rat spleen which expresses high levels of the CB2 cannabinoid receptor. Small amounts of anandamide were also detected in human heart and rat skin. Only trace quantities were detected in pooled human serum, plasma, and CSF. The distribution of anandamide in human brain and spleen supports its potential role as an endogenous agonist in central and peripheral tissues. The low levels found in serum, plasma, and CSF suggest that it is metabolized in tissues where it is synthesized, and that its action is probably not hormonal in nature.

Animals↗

PubMed1997

Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase.

Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).

Adenylyl Cyclase Inhibitors↗

PubMed1998

Arachidonylethanolamide (AEA) activation of FOS proto-oncogene protein immunoreactivity in the rat brain.

It is thought that the physiological actions of endogenous cannabinoid arachidonylethanolamide (AEA), as well as exogenous cannabinoids such as Delta9-tetrahydrocannabinol (THC), are mediated by two subtypes of cannabinoid receptors, CB1 and CB2, which have recently been characterized. Injection of AEA leads to alterations in motor behavior and endocrine function. While these phenomena have been well characterized, the neuronal substrate of AEA's actions remains undetermined. In this study, FOS immunoreactivity (FOSir) was used to map rat brain nuclei that are responsive to a single intracerebroventricular injection of AEA. The results showed that FOSir was induced in several nuclei including the bed nucleus of the stria terminalis (BNST), paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (Ce), periaqueductal gray area (PAG), dentate gyrus in the hippocampus (Dg), paraventricular nucleus of the thalamus (PVA), median preoptic nucleus (MnPO), periventricular nucleus (Pe), caudate putamen (CPU) and the ependymal lining of the ventricles. The pattern of activation identified correlates, in part, with the distribution of CB receptors. At the same time, a new subset of nuclei, without demonstrable CB receptors, have been shown to respond to an AEA challenge. Activation of these nuclei is consistent with the physiological effects of AEA. These findings provide valuable information on the response to AEA at the level of neuronal activation and provide the basis for a broader understanding of the possible role of CB receptors in the modulation of motor and endocrine function associated with the use of exogenous cannabinoids, such as marijuana.

Animals↗

PubMed2003

The effect of anandamide on prolactin secretion is modulated by estrogen.

Recent research has revealed that endogenous cannabinoid receptors (CB1 and CB2) react with the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol. Two endogenous ligands activate these receptors. The principal one, anandamide (AEA), activates CB1. AEA and CB1 are localized to various neurons within the brain. Because Delta(9)-tetrahydrocannabinol inhibited prolactin (Prl) secretion following its intraventricular injection into male rats, we hypothesized that AEA would have a similar effect. Estrogen modifies many hormonal responses and is known to increase Prl secretion. Therefore, we hypothesized that responses to intraventricular AEA would change depending on the gonadal steroid environment. Consequently, we evaluated the effects of lateral cerebral ventricular microinjection of AEA (20 ng) into male, ovariectomized (OVX), and estrogen-primed (OVX-E) rats. AEA decreased plasma Prl in male rats, had little effect in OVX females, and increased Prl in OVX-E rats. The results were at least partially mediated by changes in dopaminergic turnover, altering the inhibitory dopaminergic control of Prl release by the anterior pituitary gland. Thus, dopamine turnover was increased in the male rats and decreased significantly in OVX and in OVX-E rats. The changes in Prl may be caused not only by altered dopamine input to the anterior pituitary gland but also by effects of AEA on other transmitters known to alter Prl release. Importantly, in OVX-E rats, the elevated Prl release and the response to AEA were blocked by the AEA antagonist, indicating that AEA is a synaptic transmitter released from neurons that decrease inhibitory control of Prl release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

The third transmembrane helix of the cannabinoid receptor plays a role in the selectivity of aminoalkylindoles for CB2, peripheral cannabinoid receptor.

Two subtypes of the human cannabinoid receptor have been identified. The CB1 receptor is primarily distributed in the central nervous system, whereas the CB2 receptor is associated with peripheral tissue, including the spleen. These two subtypes are also distinguished by their ligand-binding profiles. The goal of this study was to identify critical residues in transmembrane region III (TM3) of the receptors that contribute to subtype specificity in ligand binding. For this purpose, a chimeric cannabinoid receptor [CB1/2(TM3)] was generated in which the TM3 of CB1 was replaced with the corresponding region of CB2. These receptors were stably expressed in Chinese hamster ovary cells for evaluation. The binding affinities of CB1/2(TM3) and the wild-type CB1 receptor to several prototype ligands were similar with one notable exception: the chimeric receptor exhibited a 4-fold enhancement in binding affinity to WIN 55,212-2 (K(d) = 4.8 nM) relative to that observed with CB1 (K(d) = 21.7 nM). Two additional aminoalkylindoles, JWH 015 and JWH 018, also bound the chimeric receptor (K(i) = 1.0 microM and 1.4 nM, respectively) with higher affinity compared with the wild-type CB1 (K(i) = 5.2 microM and 9.8 nM, respectively). Furthermore, the increase in binding affinities of the aminoalkylindoles were reflected in the EC(50) values for the ligand-induced inhibition of intracellular cAMP levels mediated by the chimeric receptor. This pattern mirrors the selectivity of WIN 55,212-2 binding to CB2 compared with CB1. Site-specific mutagenesis of the most notable amino acid changes in the chimeric receptor, Gly195 to Ser and Ala198 to Met, revealed that the enhancement in WIN 55,212-2 binding is contributed to by the Ser but not by the Met residue. The data indicate that the amino acid differences in TM3 between CB1 and CB2 play a critical role in subtype selectivity for this class of compounds.

Animals↗

PubMed2000

2-Arachidonoylglycerol and the cannabinoid receptors.

2-Arachidonoylglycerol (2-AG) is a unique molecular species of monoacylglycerol isolated from rat brain and canine gut as an endogenous cannabinoid receptor ligand (Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A., Waku, K., 1995. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89-97; Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N. E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Giffin, G., Bayewitch, M., Brag, J., Vogel, Z., 1995. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83-90). 2-AG binds to the cannabinoid receptors (CB1 and CB2) and exhibits a variety of cannabimimetic activities in vitro and in vivo. Recently, we found that 2-AG induces Ca(2+) transients in NG108-15 cells, which express the CB1 receptor, and in HL-60 cells, which express the CB2 receptor, through a cannabinoid receptor- and Gi/Go-dependent mechanism. Based on the results of structure-activity relationship experiments, we concluded that 2-AG but not anandamide is the natural ligand for both the CB1 and the CB2 receptors and both receptors are primarily 2-AG receptors. Evidences are gradually accumulating that 2-AG is a physiologically essential molecule, although further detailed studies appear to be necessary to determine relative importance of 2-AG and anandamide in various animal tissues. In this review, we described mainly our previous and current experimental results, as well as those of others, concerning the tissue levels, bioactions and metabolism of 2-AG.

Animals↗

PubMed1996

Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs.

The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.

Animals↗

PubMed1998

Immunohistochemical localization of the neural cannabinoid receptor in rat brain.

The cannabinoid receptor family consists of two inhibitory G-protein-coupled receptors, CB1 and CB2. CB1 is distributed primarily in neural tissue, whereas CB2 is distributed predominantly in immune cells. The distribution of cannabinoid receptors in neural tissue has been demonstrated by using ligand binding autoradiography with CP55,940, a high-affinity cannabinoid receptor ligand, and in situ hybridization. However, the localization of CB1 within individual cells in the brain remains to be defined. In the present study, domain-specific polyclonal antibody to amino acids 83-98 of CB1 was used to define the expression of the neural cannabinoid receptor at the histochemical level. The use of CB1-specific antiserum is advantageous in view of recent reports that CB2 also is expressed in the brain and binds CP55,940. Thus, utilization of anti-CB1 antiserum would allow for the specific detection of CB1 protein expression. The regional staining pattern for CB1 in rat brain was consistent with that reported for CB1 using ligand binding autoradiography and in situ hybridization. Intense immunoreactivity was present in the hippocampal formation, the basal ganglia, and the molecular layer of the cerebellum. Moderate immunohistochemical staining was observed in the olfactory bulb, piriform cortex, cerebral cortex, and the granular layer of the cerebellum. In addition, immunoreactive staining was concentrated on afferent projections and dendritic processes of neuronal cells and was present within cell bodies and on cell surfaces. These data indicate that the anti-CB1 antibody is a sensitive probe for the unequivocal histological discrimination of CB1 protein expression.

Animals↗

PubMed2006

New natural noncannabinoid ligands for cannabinoid type-2 (CB2) receptors.

Since the discovery that Delta 9-tetrahydrocannabinol and related cannabinoids from Cannabis sativa L. act on specific physiological receptors in the human body and the subsequent elucidation of the mammalian endogenous cannabinoid system, no other natural product class has been reported to mimic the effects of cannabinoids. We recently found that N-alkyl amides from purple coneflower (Echinacea spp.) constitute a new class of cannabinomimetics, which specifically engage and activate the cannabinoid type-2 (CB2) receptors. Cannabinoid type-1 (CB1) and CB2 receptors belong to the family of G protein-coupled receptors and are the primary targets of the endogenous cannabinoids N-arachidonoyl ethanolamine and 2-arachidonoyl glyerol. CB2 receptors are believed to play an important role in distinct pathophysiological processes, including metabolic dysregulation, inflammation, pain, and bone loss. CB2 receptors have, therefore, become of interest as new targets in drug discovery. This review focuses on N-alkyl amide secondary metabolites from plants and underscores that this group of compounds may provide novel lead structures for the development of CB2-directed drugs.

Cannabinoids↗

PubMed2003

CB1- and CB2-cannabinoid receptor-independent lipolysis induced by WIN 55,212-2 in male rat adipocytes.

The expression of genes encoding the cannabinoid CB(1) and CB(2) receptors and fatty acid amide hydrolase (FAAH) and the lipolytic activity of cannabinoid agonists were investigated in rat adipose tissue.RT-PCR studies indicated that the genes encoding CB(1) and CB(2) receptors and FAAH are not expressed in epididymal adipocytes. In functional studies, the non-selective cannabinoid receptor agonist WIN 55,212-2 concentration-dependently (0.01-30 micro M) induced glycerol release above baseline ( E(max) 96.1+/-6.2% of isoprenaline-induced lipolytic response). The selective CB(2) agonist JWH-015 (0.01-30 micro M) had no lipolytic activity while the endocannabinoid 2-arachidonoylglycerol and the stable anandamide derivative, R(+)-methanandamide had, only a weak lipolytic effect at the highest concentrations employed (10 and 30 micro M). The concentration/response relationship for WIN 55,212-2-mediated lipolytic activity, mimicked by the S(-)-enantiomer WIN 55,212-3, was shifted significantly to the right by the CB(1) antagonist AM 251 only at 10 micro M, but was not modified by the beta-adrenoceptor antagonist propranolol (1 micro M). The protein kinase inhibitor H-89, but not the two adenylyl cyclase inhibitors (+/-) N(6)- R-phenylisopropyladenosine (R-PIA, 1 micro M, a selective A(1) adenosine receptor agonist) or SQ 22,536 (50 micro M) significantly reduced the glycerol efflux induced by WIN 55,212-2. Our data suggest that the cannabinoid drug WIN 55,212-2 may exert lipolytic activity in male rat adipocytes via an intracellular mechanism, not activated by CB(1) or CB(2) receptor stimulation, significantly reversed by H-89 but not clearly linked to stimulation of adenylyl cyclase.

Adipocytes↗

PubMed2004

Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status.

Using two distinct anti-CB2 receptor Abs, we investigated the expression patterns of the peripheral cannabinoid receptor CB2 in human secondary lymphoid organs. Immunohistochemical analysis using an N-terminal specific anti-CB2 Ab revealed high protein expression in the germinal centers (GCs) of secondary follicles. A C-terminal specific anti-CB2 Ab, which only recognizes a nonphosphorylated inactive receptor, showed positivity in the mantle zones (MZs) and marginal zones (MGZs) of the secondary follicles where resting cells reside, and in the primary follicles. In contrast, no positivity was observed in GCs using the C-terminal Ab, suggesting that active CB2 receptors are mainly present on cells in the GCs. Dual immunohistochemical analysis revealed that B lymphocytes express the CB2 protein abundantly. In contrast to B cells in the MZ or MGZ, CB2-expressing cells in the GCs coexpress the costimulatory membrane protein CD40, which is mainly expressed in the GCs and at very low levels in the MZs and MGZs and the proliferation marker Ki-67. Using the human Raji B cell line as a model, we demonstrate in a transwell assay that moderate migration occurs upon stimulation of the CB2 receptor with the endocannabinoid 2-arachidonoylglycerol, which is enhanced by CD40 costimulation. Our findings, that GC-related cells express active CB2 and that CB2-dependent migration requires CD40 costimulation, suggest that CB2 is involved in B cell activation.

Animals↗

PubMed2006

Synthesis and biological evaluation of several structural analogs of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand.

2-Arachidonoylglycerol (2-AG (1)) is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). There is growing evidence that 2-arachidonoylglycerol plays important physiological and pathophysiological roles in various mammalian tissues and cells, though the details remain to be clarified. In this study, we synthesized several remarkable analogs of 2-arachidonoylglycerol, closely related in chemical structure to 2-arachidonoylglycerol: an analog containing an isomer of arachidonic acid with migrated olefins (2-AGA118 (3)), an analog containing a one-carbon shortened fatty acyl moiety (2-AGA113 (4)), an analog containing an one-carbon elongated fatty acyl moiety (2-AGA114 (5)), a hydroxy group-containing analog (2-AGA105 (6)), a ketone group-containing analog (2-AGA109 (7)), and a methylene-linked analog (2-AGA104 (8)). We evaluated their biological activities as cannabinoid receptor agonists using NG108-15 cells which express the CB1 receptor and HL-60 cells which express the CB2 receptor. Notably, these structural analogs of 2-arachidonoylglycerol exhibited only weak agonistic activities toward either the CB1 receptor or the CB2 receptor, which is in good contrast to 2-arachidonoylglycerol which acted as a full agonist at these cannabinoid receptors. These results clearly indicate that the structure of 2-arachidonoylglycerol is strictly recognized by the cannabinoid receptors (CB1 and CB2) and provide further evidence that the cannabinoid receptors are primarily the intrinsic receptors for 2-arachidonoylglycerol.

Arachidonic Acids↗

PubMed1998

Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors.

The cannabinoid receptor antagonist SR141716A has been suggested to be an inverse agonist at CB1 receptors in some isolated intact tissues. We found that the basal incorporation of [35S]-GTPgammaS in Chinese hamster ovary cells expressing human recombinant CB1 and CB2 receptors was inhibited by SR141716A (mean pEC50s 8.26 and 6.00, respectively), whereas cannabinol (10 microM) had no significant effect at hCB1 receptors but inhibited the binding at hCB2 receptors. As cannabinol had no effect on basal [35S]-GTPmicroS binding at hCB1 at a concentration 100 fold higher than its binding affinity (K = 0.1 microM), we conclude that endogenous cannabinoid receptor agonists are not a confounding factor and suggest the actions of SR141716A at the hCB1 receptor, and the actions of SR141716A and cannabinol at the hCB2 receptor, are due to inverse agonism.

Animals↗

PubMed2004

Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1.

The endothelium-dependent mesenteric vasorelaxant effect of anandamide has been attributed to stimulation of a Gi/Go-coupled receptor, for which the nonpsychoactive analog abnormal cannabidiol (abn-cbd, (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)olivetol) is a selective agonist and the compound O-1918 ((-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol) is a selective antagonist. In human umbilical vein endothelial cells abn-cbd was reported to increase the phosphorylation of p44/42 mitogen activated protein kinase (MAPK) and protein kinase B/Akt, and these effects could be inhibited by pertussis toxin, by phosphatidylinositol 3-kinase (PI3K) inhibitors or by O-1918 [Mol. Pharmacol. 63 (2003) 699]. In the present experiments, abn-cbd caused a concentration-dependent increase in human umbilical vein endothelial cell migration, as quantified in a transwell chamber. This effect was antagonized by O-1918, by the PI3K inhibitor wortmannin, and by pertussis toxin, but not by the cannabinoid CB1 receptor antagonist AM251 or the cannabinoid CB2 receptor antagonist SR144528. The EDG-1 receptor agonist sphingosine-1-phosphate also increased human umbilical vein endothelial cell migration, but this response was unaffected by O-1918. In Chinese hamster ovary cells stably transfected with the gene encoding the EDG-1 receptor, p44/42 MAPK phosphorylation was unaffected by abn-cbd, but strongly induced by sphingosine-1-phosphate. These results indicate that an abn-cbd-sensitive endothelial receptor distinct from cannabinoid CB1, CB2 or EDG-1 receptors mediates not only vasorelaxation but also endothelial cell migration.

Androstadienes↗

PubMed1999

Ligand-ligand and ligand-receptor approaches to modeling the cannabinoid CB1 and CB2 receptors: achievements and challenges.

The cannabinoid CB1 and CB2 receptors belong to the super family of G protein-coupled receptors. Antagonists for each receptor sub-type, as well as four structural classes of agonists that bind to both receptors, have been identified. In the absence of an experimentally determined structure for each of these two receptors, computational molecular modeling approaches have been employed to begin to probe structure-function relationships. Molecular modeling studies have been approached from two perspectives: calculations involving only ligands (Ligand-Ligand Approach) or calculations of the interaction of a ligand with its receptor macromolecule (Ligand-Receptor Approach) [49]. The Ligand-Ligand Approach does not directly consider the structure of the ligand binding site, but attempts to infer information about this site from a correlation between experimentally determined biological activities and the structural and electronic features of a series of small molecules. Ligand-Ligand Approaches result in development of pharmacophore models. Although closer to the event of interest, the study of the binding of a ligand to its receptor is less common because it requires a working knowledge of the receptor structure [54]. Mutation/ chimera studies, as well as structure activity relationships can be used to test models developed in a Ligand-Receptor Approach. This review considers both Ligand-Ligand and Ligand-Receptor computational studies of the CB1 and CB2 receptors. Challenges for further modeling studies are also identified.

Amino Acid Sequence↗