Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular biology has a strong impact on current research into drug and alcohol dependence. Spectacular recent results include the cloning of a cannabinoid receptor, nicotine receptors in the CNS and the targets of amphetamine and cocaine action, catecholamine transporters. Alcohol has been found to interact with the GABAA and NMDA (glutamate) receptors at concentrations reached with social alcohol use. The interactions of opiates and other drugs of abuse with the endogenous opioid peptides have been studied at several levels; it is a general finding that precursor gene transcription is suppressed. Although much less is known about the molecular consequences of chronic addictive drug usage, a functional deficit in opioid systems has been described. A general addiction mechanism may have similarities with memory storage mechanisms which are currently being studied with molecular probes.
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PMID:[Molecular neurobiological research in the fight against drug abuse]. 165 Aug 71

It has been shown that the main psychoactive component of marihuana, delta 9-tetrahydrocannabinol (THC) has mainly inhibitory effects on pituitary luteinizing hormone (LH), prolactin (PRL) and growth hormone (GH) and has no or little effect on follicle stimulating hormone (FSH) secretion. Recently the purification and availability of the putative endogenous ligand for the cannabinoid receptor, anandamide (arachidonyl ethanol-amide, anandamide) (ANA) provided us the opportunity to compare the effects of THC and ANA on the female neuroendocrine system in ovariectomized (OVX) rats. OVX was performed three weeks prior to the experimental period to avoid cyclic differences. OVX rats were injected i.p. with either THC or ANA (0.02 mg/kg.b.w./day, respectively) or vehicle for two weeks. The results show that both ANA and THC decrease serum LH level although THC with a higher degree. No significant differences were observed in serum FSH level. Both drugs decreased serum PRL. Serum GH was increased after THC administration and significantly decreased after ANA. The results indicate that ANA and THC alter pituitary hormone secretion, mainly by inhibitory action. The site of action requires further investigations.
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PMID:Effects of anandamide (endogen cannabinoid) on anterior pituitary hormone secretion in adult ovariectomized rats. 777 32

The basic premise underlying the cannabinoid pharmacophore is that at least three functional groups are involved in the interaction between the ligand and the receptor and that these functional groups in delta 9-THC comprise (a) C11, (b) the phenolic hydroxyl, and (c) the side chain. In order to assess the relative importance of the C11 position and the side chain, a series of C11 substituted analogs were prepared which contained a dimethylheptyl side chain. Consistent with previous studies, incorporation of a dimethylheptyl side chain dramatically enhanced both pharmacological potency in mice and receptor affinity. Incorporation of a hydroxy at C11 along with this branched side chain resulted in an extremely potent cannabinoid with ED50S of 0.01, 0.04, 0.16 and 0.04 mumol/kg in depression of spontaneous activity, reduction in body temperature, antinociception, and immobility, respectively. This compound was also very potent as a discriminative stimulus in a drug discrimination procedure and exhibited an extended duration of action. Its high affinity for the cannabinoid receptor (Ki = 400 pM) was consistent with this pharmacological potency. Incorporation of an oxo rather than a hydroxy reduced potency somewhat, although this analog was much more potent than delta 9-THC in most behavioral assays. The most striking observation was that incorporation of a carboxylic acid to form 11-nor-delta 9-THC-DMH-9-carboxylic acid did not eliminate pharmacological activity. This analog was as potent as delta 9-THC. The improbability that all three of the functional groups are interacting in a similar fashion with the receptor provides further support that the C11 position is not an essential requirement for activity. On the other hand, it is possible that substituents in the C9 region are interacting somewhere within or near the same site, but differently.
Drug Alcohol Depend 1995 Mar
PMID:Pharmacological evaluation of dimethylheptyl analogs of delta 9-THC: reassessment of the putative three-point cannabinoid-receptor interaction. 779 17

Despite a large body of research directed at assessing the effects of perinatal cannabinoid exposure, little is known about the development of the cannabinoid receptor. Recent advances, including the cloning of the cannabinoid receptor, have afforded us the opportunity to plot the postnatal ontogeny of the cannabinoid receptor and its mRNA in whole brain using the methods of receptor binding and RNA blot hybridization, respectively. Our results indicate that cannabinoid receptor mRNA is present at adult levels as early as postnatal day 3. The Bmax, on the other hand, increases almost fifty percent with increasing postnatal age, while the affinity does not change. The Hill coefficients for all ages studied were approximately 1. These findings suggest the possibility of a developmental progression for cannabinoid receptor development with receptor mRNA appearing first, followed by a period of rapid proliferation of the receptors themselves.
Drug Alcohol Depend 1994 Aug
PMID:Cannabinoid receptors in developing rats: detection of mRNA and receptor binding. 798 56

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

A polyenoic fatty-acid isomerase (PFI) from a red marine alga was used to convert anandamide (5Z,8Z,11Z,14Z-eicosatetraenoyl-N-ethan olamide) to the 5Z,7E,9E,14Z-eicosatetraenoyl-N-ethanol amide isomer. This novel eicosanoid, termed conjugated triene anandamide (CTA), was assessed for its ability to bind to the cannabinoid receptor in rat brain membrane preparations. CTA is a high affinity cannabimimetic substance whose novel structure provides new insight into structure-activity relationships of cannabinoid receptor ligands. These experiments illustrate the utility of enzymes isolated from marine organisms in the development of pharmacological probes.
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PMID:Synthesis and cannabinoid receptor binding activity of conjugated triene anandamide, a novel eicosanoid. 857 65

The endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), has been shown to produce antinociception using the tail-flick test following intrathecal administration. Anandamide was administered i.p. (40 mg kg) to mice four times per day for 3 days. Tolerance developed to anandamide: the ED50 for anandamide (i.t.) was shifted from 40 (26-61) to 139 (79-248) micrograms/mouse. Anandamide-tolerant mice were cross-tolerant to delta 9-THC and CP55,940, but not cross-tolerant to mu-, delta- or kappa- opioids, including dynorphins. Conversely, delta 9-THC-tolerant mice are cross-tolerant to anandamide, CP55,940 and kappa agonists. Our data indicate that anandamide and delta 9-THC differ in the mechanisms by which they induce tolerance, in particular the interaction with endogenous dynorphinergic systems.
Drug Alcohol Depend 1997 Apr 14
PMID:Characterization of anandamide-induced tolerance: comparison to delta 9-THC-induced interactions with dynorphinergic systems. 917 5

SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL/6 mice. In contrast, blockade of CB1 receptors only marginally affects regular chow intake or water drinking. The active doses of SR 141716 (0.3-3 mg/kg) are in the range known to antagonize the characteristic effects induced by cannabinoid receptor agonists. These results suggest for the first time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by affecting the activity of brain reward systems.
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PMID:Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. 927 66

The present study was designed to test the possible existence of changes in brain cannabinoid receptors in morphine-dependent mice. To this end, we compared cannabinoid receptor binding and WIN 55,212-2-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding in several brain regions of mice chronically exposed to morphine or saline. The existence of opiate dependence in morphine-injected mice was assessed by analyzing the well-known jumping behavior induced by the blockade of opioid receptors with naloxone, whereas these animals were unresponsive to the blockade of cannabinoid receptors with SR141716. The different structures analyzed exhibited similar cannabinoid receptor binding levels in morphine-dependent and control mice, with the only exception of the globus pallidus, which exhibited a very small, but statistically significant, increase. In addition, the activation of cannabinoid receptors with WIN 55,212-2 increased [35S]GTP gamma S binding in most of the structures examined. The increase was of similar magnitude in morphine-dependent and control mice, except in the substantia nigra, where morphine-dependent mice exhibited lesser [35S]GTP gamma S binding levels in basal conditions, although a significantly higher WIN 55,212-2-stimulated binding. Other structures, such as the central gray substance, where there was a poor agonist-induced stimulation in control mice, exhibited, however, higher levels of WIN 55,212-2-stimulated [35S]GTP gamma S binding in morphine-dependent mice, whereas these animals tended to exhibit a higher [35S]GTP gamma S binding levels in basal conditions, although a lesser and not statistically significant WIN 55,22-2-stimulated binding, in the deep layers of the cerebral cortex. Thus, the data support the potential existence of a specific effect of morphine in the coupling of cannabinoid receptors to GTP-binding proteins, rather than on receptor binding, although this was observed only in the substantia nigra and central gray substance.
Drug Alcohol Depend 1998 May 01
PMID:Autoradiographic analysis of cannabinoid receptor binding and cannabinoid agonist-stimulated [35S]GTP gamma S binding in morphine-dependent mice. 964 78

Many drugs cannot be dissolved in distilled water and so other solvents such as ethanol, dimethylsulphoxide and methanol are used. Because very little is known about the direct effects of these three solvents on the cardiovascular system, we have examined their effects on isolated pulmonary and coronary arteries from the pig. Increasing concentrations of ethanol, dimethylsulphoxide and methanol induced relaxation in porcine pulmonary (at 1.2% v/v, 59.9+/-9.0% (n =9), 55.9+/-9.0% (n =6) and 12.3+/-6.4% (n = 8), respectively, of U46619-induced tone) and coronary arteries (at 1.2% v/v, 69.9+/-7.1% (n = 10), 78.9+/-6.1% (n = 7) and 12.9+/-8.2% (n = 6) respectively, of U46619-induced tone). In the pulmonary arteries the relaxation in response to ethanol was found to be endothelium-dependent whereas the responses to dimethylsulphoxide and methanol were unaffected by removal of the endothelium. In the coronary arteries the relaxation to all three solvents was independent of the presence of the endothelium. Comparison of the sensitivity of the tissues to the solvents showed that ethanol and dimethylsulphoxide produced comparative responses in both the pulmonary and coronary arteries, whereas methanol was much less potent. The endothelium-dependent response to ethanol in the porcine pulmonary artery (maximum response, Emax, 67.1+/-9.3% of U46619-induced tone, n = 7) was attenuated by the cyclooxygenase inhibitor, flurbiprofen (Emax 31.9 +/- 12.0%, n=7), the nitric oxide synthase inhibitor, L-NAME (NG-nitro-L-arginine methyl ester; Emax 23.5+/-10.2%, n = 7)) and the combination of both inhibitors (Emax 18.3+/-7.8%, n = 7). The residual relaxatory response to ethanol was abolished, and converted into a contractile response, both by removal of the endothelium (at 1.7% v/v ethanol 27.3+/-11.5% of U46619-induced tone, n=7) and by the addition of a low concentration of KC1 (49.9-/+10.3%, n=6), suggesting the release of a non-prostanoid, non-nitric oxide factor from the endothelium. This response, however, was not attenuated by the cannabinoid receptor-antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide HCL; 52.5-/+4.3% relaxation, n =8), suggesting that the factor released in this preparation by ethanol is not a cannabinoid. The results of this study indicate that many solvents commonly used in pharmacological experiments have pronounced vasoactive properties. Methanol might be the vehicle of choice, because it was the least active solvent, whereas high concentrations of ethanol might influence vascular function at both the level of the smooth muscle and the endothelium, with the action on the endothelium involving the release of endothelium-derived relaxing factors.
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PMID:Endothelium-dependent relaxation in response to ethanol in the porcine isolated pulmonary artery. 975 53


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