Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabimimetic compounds, such as delta 9-tetrahydrocannabinol (delta 9-THC), evoke analgesia in addition to other behavioral responses in humans and animals. The cannabinoid receptor mediating this response has been characterized by its ability to bind the cannabinoid agonist [3H]CP-55,940 and to inhibit adenylyl cyclase via Gi. An investigation of structural requirements for antinociceptive activity of cannabinoid structures led to the development of a simple bicyclic cannabinoid agonist, CP-47,497, that possessed a spectrum of cannabinoid activities in animals that resembled that of delta 9-THC. The present investigation examines several series of CP-47,497 analogs for their binding affinity at the cannabinoid receptor and their ability to evoke analgesia in rodents. Analogs substituted at the C-3 alkyl side chain exhibited maximal affinity for the cannabinoid receptor with side chains of seven or eight carbons in length. Analgesic potency paralleled the receptor-binding affinity. The cyclohexyl ring was optimized as a six- or seven-membered ring structure for binding as well as analgesic activity. Cyclohexyl alkyl side chain extensions of up to four carbons in length had little influence on the affinity for the receptor or analgesic activity. Hydroxyalkyl side chains exhibited optimal binding affinity and antinociceptive activity at three or four carbon atoms in length; however, polar groups closer to the ring diminished binding to the receptor. The importance of the phenolic and cyclohexyl hydroxyl groups for binding affinity was demonstrated. In general, analgesic activity correlated well with the affinity of these analogs for the cannabinoid receptor. Exceptions could be explained by metabolic transformations likely to occur in vivo.
Mol Pharmacol 1993 Nov
PMID:Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. 824 4

The lipid composition of the brain is of great importance to its metabolism and function. Although much research has been done on regional brain lipid composition, studies usually suffer from limited brain regions or from limited lipids analyzed. We modified a previously described method for the separation of brain phospholipids and glycolipids, improving the separation and sensitivity of the method. Using this modified method, we measured the lipid composition of the frontal and entorhinal cortices, the hippocampus, basal ganglia, cerebellum, and medulla oblongata of five rats under nitrous oxide analgesia. Total lipid content was highest (p < 0.05) in the medulla oblongata (111.0 +/- 6.0 mg/g wet brain, X +/- SD) followed by the hippocampus (72.6 +/- 2.8), cerebellum (62.7 +/- 4.6), basal ganglia (62.6 +/- 1.5), frontal cortex (57.7 +/- 2.1), and entorhinal cortex (53.3 +/- 1.9). The areas with higher total lipid content (p < 0.05) also had higher percentages of cerebrosides (18.6 +/- 2.2 in the medulla oblongata vs 8.3 +/- 1.2 in the frontal cortex) and 40 to 50% lower levels of phosphatidylcholine and phosphatidylinositol. The relation between the ratio of cerebrosides plus sulfatides to phosphatidylcholine and the total lipid content indicates that differences in brain lipid composition between regions are attributable to their relative gray/white matter content.
Mol Chem Neuropathol
PMID:Regional lipid composition in the rat brain. 846 86

In a group of mice bearing experimentally induced tumors, the protein binding of mianserin in vitro was measured and compared with a control group. The analgesic effect and the brain uptake of drug was also compared with a control group after an intraperitoneal dose of mianserin. The unbound percentage of mianserin in the plasma of mice with experimental cancer decreased with respect to control animals (5.20 +/- 0.12 vs 6.06 +/- 0.26; p<0.05) and alpha1-acid glycoprotein (AAG) levels, measured as plasma mucoprotein concentrations, were significantly increased (p<0.05). The brain/plasma drug concentration ratio of mianserin decreased in mice with experimental cancer when compared with control mice (1.11 +/- 0.03 vs 1.42 +/- 0.10; p<0.02). In both groups of mice, the mianserin analgesic effect was evaluated by the hot plate test after intraperitoneal drug administration. When the analgesia response-dose curve (0-60 mg/kg) was studied, a significant decrease in the response in mice with experimental cancer versus control mice was observed. These results suggest that resistance to the mianserin analgesic response may occur in animals with cancer disease. This resistance may be associated, in part, with an altered plasma protein binding, but other mechanisms could be involved.
Res Commun Mol Pathol Pharmacol 1995 Sep
PMID:Changes in the analgesic effects of mianserin associated with altered plasma protein binding in experimental cancer. 868 Aug 2

Antisense oligodeoxynucleotides directed against various G protein alpha subunits differentially block the analgesic actions of mu-, delta-, and kappa-opioid agonists in mice. Intracerebroventricular administration of oligodeoxynucleotides targeting Gi alpha 2, G(o) alpha, and Gs alpha block supraspinal mu-opioid analgesia, whereas Gi alpha 2 and Gx/z alpha antisense probes block spinal mu analgesia. Although supraspinal and spinal morphine-6 beta-glucuronide (M6G) analgesia also is sensitive to these antisense treatments, its sensitivity profile differs from that of morphine, implying the existence of a different analgesic system. Gi alpha 1 and Gx/z alpha antisense probes block supraspinal M6G analgesia, whereas Gi alpha 1, Gi alpha 3, G(o) alpha, and Gx/z alpha antisense probes block spinal M6G analgesia. Spinal delta-opioid analgesia is blocked by antisense probes to all of the G protein alpha subunits tested, whereas kappa 1-opioid analgesia is sensitive to only Gq alpha. The kappa 3 agonist naloxone benzoylhydrazone produces its analgesia through supraspinal mechanisms and is blocked by Gi alpha 1, Gi alpha 3, Gs alpha, Gq alpha, and Gx/z alpha antisense oligodeoxynucleotides. Together, these results support the presence of seven different analgesic systems for these various opioid agonists.
Mol Pharmacol 1996 Aug
PMID:Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits. 870 Jan 36

Incubation of highly enriched neurons from rat cerebral cortex with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 18 h results in fragmentation of DNA at internucleosomal linkers, a feature of apoptosis. We report that neurons respond to exposure to gp120 with an increased release of arachidonic acid via activation of phospholipase A2. This process is not inhibited by antagonists of the N-methyl-D-aspartate (NMDA) receptor channels. To investigate the influence of arachidonic acid on the sensitivity of NMDA receptor towards its against, low concentrations of NMDA were coadministered with arachidonic acid. Under these conditions the NMDA-mediated cytotoxicity was enhanced. We conclude that gp120 causes an activation of phospholipase A2, resulting in an increased release of arachidonic acid which in turn sensitizes the NMDA receptor. Two compounds were found to act cytoprotectively against the deleterious effect caused by gp120 on neurons: Memantine [1-amino-3,5-dimethyladamantane] and Flupirtine [2-amino-3-ethoxycarbonylamino-6-(4-fluoro-benzyl-amino)-pyridine maleate]. Both compounds have been found to display a potent cytoprotective effect on neurons treated with the excitatory amino acid NMDA or with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120. The NMDA antagonist Memantine, a drug currently used in the therapy of spasticity and Parkinson's disease, prevented the effects of gp120 at micromolar concentrations. Flupirtine was previously found to be a centrally acting, nonopiate analgesic agent which additionally possesses anticonvulsant and muscle-relaxant activity at doses similar to those producing analgesia. The cytoprotective effect of Flupirtine in vitro was significant (above 10 microM). Considering the fact that both Memantine and Flupirtine display almost no clinical side effects, these drugs may prove useful both in preventing primary infection of brain cells with the HIV virus, as well as in treating the neurological disorders often associated with the immunodeficiency syndrome such as AIDS-related dementia.
Prog Mol Subcell Biol 1996
PMID:Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention. 882 91

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that is indicated for the short-term management of moderately severe, acute pain, that causes analgesia equivalent to that caused by morphine. It has been shown experimentally that the analgesia produced by ketorolac in mice can be diminished by pretreatment with naloxone. This observation suggests that ketorolac produces some of its analgesia by interacting with opioid receptors. However, ketorolac does not directly interact with opioid receptors (Lopez et al., 1987). The present experiments demonstrate that the analgesia produced by ketorolac may be caused by the release of the endogenous opioid, methionine-enkephalin.
Res Commun Mol Pathol Pharmacol 1996 Feb
PMID:Ketorolac causes the release of methionine-enkephalin in rats. 883 17

Previous studies of the structure-activity relationships (SAR) for binding of a series of AC-bicyclic cannabinoid structures to the cannabinoid receptors in rat brain (believed to comprise the CB1 subtype) demonstrated the importance of the A-ring aryl C-3 side chain and phenolic hydroxyl substituents, and elucidated the importance of a C-ring hydroxyalkyl substituent [Melvin et al. Mol. Pharmacol. 44, 1008-1015 (1993)]. The present investigation examines the SAR surrounding this region (D-ring) of the molecule that is not present in the structure of delta(9)-THC and other classical cannabinoid compounds. Both rigid fused ring benzo and cyclohexyl derivatives (creating the D-ring) retained binding affinity for the cannabinoid receptor. Extension of ketone or hydroxyl substituents from the C2 position of the D-ring resulted in a 3-fold increase in binding affinity over the unsubstituted structure. However, the fused ring structure is not critical for the interaction with the receptor in as much as opening the ring did not decrease the potency. Extension of the D-ring C-2 alcohol by one carbon in length resulted in a pair of structures, for which the greatest affinity for the CB1 receptor occurred for the hydroxymethyl group in the axial conformation [(+/-)-CP-55,244]. Upon resolution, the latter provided a pair of enantiomers: (-)-CP-55,244 was approximately 3-fold more potent than the racemic mixtures, and (+)-CP-55,244 failed to bind to the CB1 receptor with an IC50 below 1 mM. Opening of the D-ring of these structures resulted in a loss of binding affinity. This study demonstrates that the potency could be optimized in (-)-CP-55,244 for both binding to the CB1 receptor and the biological activity of analgesia. In addition, the rigid positioning of the hydroxypropyl moiety of CP-55,940 enforced by the decalin ring structure of CP-55,244 increased the enantioselectivity by greater than 100-fold. These data define the critical stereochemistry for a region of the nonclassical ACD-tricyclic cannabinoid structure that contributes a potential hydrogen bonding component to the ligand-receptor interaction mechanism. Inasmuch as this region of the molecule is not present on classical ABC-tricyclic cannabinoid compounds, these studies elucidate a unique agonist recognition site on the CB1 receptor.
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PMID:Structure-activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity. 887 58

Low and high frequency electroacupuncture (EA)-produced analgesia have been shown to be mediated by different brain substrates and different opioid peptides. In this study, Fos-like immunoreactivity (FLI) and in situ hybridization of the three opioid mRNAs were used to examine the effect of low (2 Hz) and high (100 Hz) frequency EA on neuronal activities, and the expression of opioid genes. 2 Hz and 100 Hz EA induced a markedly different spatial patterns of Fos expression in the rat brain, suggesting there are distinct neuronal pathways underlying EA of different frequencies. Likewise, 2 Hz and 100 Hz EA exert differential effects on opioid gene expression: while 2 Hz EA induced a more extensive and intensive preproenkephalin (PPE) mRNA expression than 100 Hz EA, it had no effect on preprodynorphin (PPD) mRNA expression which was significantly increased by 100 Hz EA stimulation. In contrast, EA of both frequencies did not affect POMC mRNA expression.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Brain substrates activated by electroacupuncture of different frequencies (I): Comparative study on the expression of oncogene c-fos and genes coding for three opioid peptides. 903 29

Prolonged exposure of rats to the synthetic cannabinoid receptor ligand, CP-55,940 (0.4 mg/kg, i.p. for 11 days), induced tolerance to analgesia, to the reduction in spontaneous locomotor activity and the incidence of splayed hind limbs. One hour after the last injection on day 11, the rats were killed and in situ hybridization was used to investigate the effect of treatment on G-protein alpha-subunit expression throughout the brain. Chronic cannabinoid exposure markedly reduced G alpha(s), G alpha(i) and G alpha(o) mRNA levels. The message for the alpha(s)-subunit was decreased in all the brain areas containing the basal autoradiographic signal; the decrease ranging from 25% in the thalamus to 45% in the mesencephalon. Also the basal G alpha(i) expression was reduced in tolerant rats showing the greatest decrease in the forebrain (63%) in the cerebellum (58%) and in the mesencephalon (38%). The reduction in G alpha(o) expression (25%) was more localized, being present only in the rostral portion of the brain (cortex, striatum and olfactory area). The alterations in alpha-subunits gene expression were not followed by any change in the amount of proteins. Our results indicate that, besides the receptor modification, alteration to the G-protein expression could be a molecular event associated with the development of cannabinoid tolerance.
Brain Res Mol Brain Res 1997 Mar
PMID:Chronic treatment with a synthetic cannabinoid CP-55,940 alters G-protein expression in the rat central nervous system. 907 60

Four different stereoisomers of cyclopropylphenylalanine (inverted delta Phe) were incorporated into [D-Ala2,Leu5]enkephalin at the position 4. These conformationally restricted enkephalin analogs were evaluated for their binding characteristics to mu and delta opioid receptors in rat brain. A striking finding is that the E-(2R,3S)-isomer binds to a novel class of delta receptors and discriminates this receptor from the ordinary delta receptor. This new type of delta receptor suspected to be a receptor which suppresses the thermal analgesia mediated through mu receptor. The Z-(2R,3R)-isomer was very potent with several times more enhanced affinity to delta receptors than to mu receptors, but could not differentiate the delta receptors. The Z-(2S,3S)-isomer was weak, and E-(2S,3R)-isomer was almost inactive.
Biochem Mol Biol Int 1997 Sep
PMID:Discrimination of a novel type of rat brain delta opioid receptors by enkephalin analog containing structurally constrained cyclopropylphenylalanine (inverted delta Phe). 930 40


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