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

The cannabinoid receptor that has been pharmacologically characterized for hypothermia, spontaneous activity, analgesia and catalepsy in rodents is the same pharmacological receptor that inhibits adenylate cyclase in vitro. The inhibition of adenylate cyclase by the cannabinoid receptor results from an interaction with Gi, based on the biochemical kinetic properties of the response, the sensitivity to pertussis toxin ADP-ribosylation, and the thermodynamic characteristics of the response. From precedents based on studies of the well-characterized G protein coupled receptors, rhodopsin and the beta-adrenergic receptor, we can predict the tertiary structure of the cannabinoid receptor. Three sites of potential glycosylation are present on the receptor. However, treatment of N18TG2 neuroblastoma cells with tunicamycin to prevent glycosylation of newly synthesized receptors failed to alter cannabinoid-induced inhibition of cyclic AMP accumulation. The cannabinoid response was rapidly desensitized (within 1/2 h). Treatment of cells with tunicamycin failed to alter agonist-induced desensitization processes. These findings can be more veraciously interpreted as we gain a better understanding of the cellular dynamics of the cannabinoid receptor.
 ...
PMID:The cannabinoid receptor: biochemical and cellular properties in neuroblastoma cells. 180 46

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.
 ...
PMID:Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. 824 4

Anandamide (arachidonylethanolamide) is a brain constituent which binds to the cannabinoid receptor. We now report the first in vivo examination of this ligand. Anandamide administered i.p. in mice, caused lowering of activity in an immobility and in an open field test, and produced hypothermia and analgesia. These effects parallel those caused by psychotropic cannabinoids.
 ...
PMID:Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. 838 16

In this study we examined whether tolerance develops to chronic exposure to anandamides [20:4, n-6 (ANA) and 20:3, n-6 (HLEA)] two of the recently discovered endogenous cannabinoid receptor ligands in brain. Tolerance to ANA and cross-tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was examined in female Sabra or C57BL/6 mice which had received daily injections (i.p.) of low (0.001-1 mg/kg) or high doses (20 mg/kg) of ANA or HLEA for 2 weeks. Twenty four h after the last injection, the mice were challenged with 20 mg/kg ANA or delta 9-THC. Animals were subjected to a series of tests frequently used to assess cannabinoid-induced effects. The results indicated that the high dose, but not the low doses of anandamides produced tolerance to ANA and cross-tolerance to delta 9-THC for motor activity in an open field, catalepsy on a ring, hypothermia and analgesia on a hot plate. One week after the last ANA treatment, tolerance was not present anymore. No tolerance to ANA was observed for reduced defecation in the open field, a measure of intestinal hypomotility. This phenomenon may possibly be attributed to a difference between activities produced through different types of cannabinoid receptors.
 ...
PMID:Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol. 859 98

Studies using agonists from at least three major cannabinoid ligand groups suggest the mediation of several distinct effects (e.g. psychotropic, analgesia, and antiemetic) by the recently cloned CB1 cannabinoid receptor. However, other studies suggest the presence of multiple cannabinoid receptors and at least one other receptor (CB2) has been cloned. The present investigation was undertaken to determine whether one of the potential therapeutic actions of cannabinoids (i.e. antinociception) is mediated by the CB1 receptor using the antisense oligodeoxynucleotide 'knock-down' approach. Synthetic oligodeoxynucleotides complementary to the 5' end of the coding region of the mouse CB1 receptor mRNA were administered to mice by the intracerebro-ventricular (i.c.v.) route twice daily for 3 days. Mismatch oligodeoxynucleotides of similar sequence, but containing six mismatched positions out of the 18 nucleotides within the oligodeoxynucleotide were administered to other mice. Treatment with antisense oligodeoxynucleotides, but not mismatched oligodeoxynucleotides, greatly inhibited the antinociceptive response of the cannabinoid agonist CP-55,940. Untreated mice and those treated with mismatched oligodeoxynucleotides showed similar, full response antinociception after CP-55,940 administration. The data provides strong evidence that the CB1 receptor-ligand interaction is essential for the antinociceptive effect.
 ...
PMID:Antisense oligodeoxynucleotide treatment to the brain cannabinoid receptor inhibits antinociception. 873 Aug 37

We have previously shown that the endogenous putative cannabinoid ligand arachidonylethanolamide (anandamide, 20:4, n - 6) induces in vivo and in vitro effects typical of a cannabinoid agonist. We now report that two other endogenous anandamides, docosatetraenylethanolamide (anandamide, 22:4, n - 6) and homo-gamma-linolenylethanolamide (anandamide, 20:3, n - 6), have similar activities. The new anandamides bind to SV40-transformed African green monkey kidney cells transfected with the rat brain cannabinoid receptor cDNA and display K1 values of 253.4 +/- 41.1 and 244.8 +/- 38.7, respectively. The value found for arachidonylethanolamide was 155.1 +/- 13.8 nM. In addition, the new anandamides inhibit prostaglandin E1-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells transfected with the cannabinoid receptor, as well as in N18TG2 mouse neuroblastoma cells that express the cannabinoid receptor naturally. The IC50 values for the inhibition of adenylate cyclase in transfected Chinese hamster ovary-K1 cells were 116.8 +/- 8.7 and 109.3 +/- 8.6 nM for docosatetraenylethanolamide and homo-gamma-linolenylethanolamide, respectively. These values were similar to that obtained with arachidonylethanolamide (100.5 +/- 7.7 nM), but were significantly higher than the IC50 value observed with the plant cannabinoid delta9-tetrahydrocannabinol (9.2 +/- 8.6 nM). The inhibitory effects of the anandamides on adenylate cyclase activity were blocked by pertussis toxin, indicating the involvement of pertussis toxin-sensitive GTP-binding protein(s). In a tetrad of behavioral assays for cannabinoid-like effects, the two new anandamides exerted similar behavioral effects to those observed with delta9-tetrahydrocannabinol and arachidonylethanolamide: inhibition of motor activity in an open field, hypothermia, catalepsy on a ring, and analgesia on a hot plate.
 ...
PMID:Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides. 874 28

delta 9-tetrahydrocannabinol elicits analgesia in rodents by both spinal and supraspinal mechanisms. Pharmacological data point to a link between cannabinoids and the opioid system. The lack of specific cannabinoid receptor antagonists has hindered the investigation of the physiological relevance of the cannabinoid system in nociception control. In this work we characterized the effect of the new cannabinoid receptor antagonist, SR-141,716 A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3- pyrazolecarboxamide hydrochloride), on delta 9-tetrahydrocannabinol-induced analgesia. pA2 values in the tail-flick and in lick and jump responses in the hot-plate tests were 9.59, 8.72 and 10.21, respectively. Slope values of pA2 plots were not different from -1 indicating competitive antagonism. The involvement of the opioid system in delta 9-tetrahydrocannabinol-induced analgesia was investigated by using naloxone as well as delta (naltrindole)- and kappa (nor-binaltorphimine)-opioid receptor antagonists. Intrathecal nor-binaltorphimine antagonized the effect of delta 9-tetrahydrocannabinol. The effect of delta 9-tetrahydrocannabinol was also blocked by administration of dynorphin A-(1-8) antiserum in the same test.
 ...
PMID:A role for central cannabinoid and opioid systems in peripheral delta 9-tetrahydrocannabinol-induced analgesia in mice. 877 49

Recent breakthroughs in cannabinoid research, including the identification of two cannabinoid receptors (CB receptors) and a family of endogenous ligands, the anandamides, may shed new light on the sequelae of pre- and perinatal exposure to cannabinoid receptor ligands and enable the experimental manipulation of the endogenous ligand in the developing organism. In the present study we examined the behavioural response to anandamide (ANA) in developing mice from day 13 into adulthood. We observed that depression of ambulation in an open field and the analgetic response to ANA are not fully developed until adulthood. In a separate set of experiments, we administered five daily injections of ANA (SC, 20 mg/kg) during the last trimester of pregnancy. No effects on birth weight, litter size, sex ratio and eye opening were detected after maternal ANA treatment. Further, no effects on open field performance of the offspring were observed until 4 weeks of age. However, from 40 days of age, a number of differences between the prenatal ANA and control offspring were detected. Thus, the offspring from ANA-treated dams showed impaired responsiveness to a challenge with ANA or delta 0-THC expressed as a lack of immobility in the ring test for catalepsy, hypothermia and analgesia. On the other hand, without challenge, they exhibited a spontaneous decrease in open field activity, catalepsy, hypothermia and a hypoalgetic tendency. These data suggest that exposure to excessive amounts of ANA during gestation alters the functioning of the ANA-CB receptor system. Further experiments investigating responsivity of the immune system suggest an increased inflammatory response to arachidonic acid, and enhanced hypothermic response to lipopolysaccharide in prenatally treated offspring. The results are discussed in relation to other manipulations of the maternal milieu, especially prenatal stress. It is concluded that alterations induced by prenatal exposure to ANA, cannabinoids and other psychotropic drugs or prenatal stress, share common features, but the data also suggest specific effects on the ANA-CB receptor system.
 ...
PMID:Developmental aspects of anandamide: ontogeny of response and prenatal exposure. 877 60

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.
 ...
PMID:Structure-activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity. 887 58

We studied the ontogenetic response to cannabinoid receptor ligands by measuring motor activity and analgesia in response to anandamide or delta 9-THC from day 6 of age. No response to anandamide was observed up to the age of weaning (day 23), while a nonsignificant response to delta 9-THC was observed starting between days 15 and 20. This is compatible with observations that children respond to the antiemetic effects of THC without psychotropic side effects.
 ...
PMID:Ontogenetic development of the response to anandamide and delta 9-tetrahydrocannabinol in mice. 887 85


1 2 3 4 5 6 7 8 9 10 Next >>