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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six novel aminoalkylindole analogs, related structurally to the dual cyclooxygenase inhibitor and nonopioid analgesic pravadoline, were evaluated in the mouse to determine whether their pharmacological profile of activity was similar to that exhibited by delta 9-tetrahydrocannabinol (delta 9-THC). Analog I (C2-H; C3-methoxy-benzoyl) reduced locomotion, but had no other effects (hypothermia, antinociception or ring-immobility) up to 21 mumol/kg. Analogs II and III (C3-naphthoyl; C2-H and C2-methyl, respectively) possessed all properties exhibited by delta 9-THC with ED50 values ranging from 0.68 to 18 mumol/kg. Analog IV (C2-methyl; C3-anthroyl) was devoid of activity. Stereoselectivity was demonstrated by the fact that (+)-WIN-55,212 (one isomer of a semirigid derivative possessing C2-H and C3-naphthoyl substituents) was moderately potent in all tests (ED50 values ranging from 0.25-23 mumol/kg), but (-)-WIN-55,212 was inactive up to 57 mumol/kg. Active aminoalkylindole compounds were generally least effective in the production of hypothermia. Analogs were also evaluated for their ability to produce delta 9-THC-like discriminative stimulus effects in rats. The ED50 for delta 9-THC as a discriminative stimuli for this model was 1.9 mumol/kg. Analog II and III and (+)-WIN-55,212 produced delta 9-THC-like discriminative effects with ED50 values ranging from 0.33 to 4.3 mumol/kg, whereas analogs I, IV and (-)-WIN-55,212 did not. Although reported to be cannabinoid receptor antagonists in vitro, neither analog I, analog IV nor (-)-WIN-55,212 (at 20 mumol/kg) antagonized the in vivo pharmacological effects of delta 9-THC in the mouse or rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. 133 57

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.
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PMID:The cannabinoid receptor: biochemical and cellular properties in neuroblastoma cells. 180 46

In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.
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PMID:Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens. 761 43

A series of 3-alkyl-2'-yne (side chain) acetylenic analogs of delta 9-THC were synthesized and evaluated for in vitro and in vivo activity. Analogs were evaluated for receptor affinity in a [3H]CP-55,940 displacement assay and for in vivo pharmacological activity in a mouse procedure utilizing a tetrad of measures. These compounds represent a preliminary exploration of the consequences of restricting the flexibility of the side chain regarding cannabimimetic activity. All analogs proved to have receptor affinities (4-11 nM) that were five to ten times greater than that observed for delta 9-THC. However, the in vivo activities of these compounds varied greatly. All analogs proved to possess the greatest potency for production of antinociception, with activity similar to or less than that observed for the production of hypomotility, hypothermia, and catalepsy. The most potent analog 11b exhibited an ED50 of 0.031 mg/kg in the tail-flick procedure, with values in other measures being between 0.5 and 1.0 mg/kg. The least active compound (11c), though still possessing a KI of 11 nM, exhibited ED50 values of 3.1 and 9.3 mg/kg for tail-flick and temperature procedures, as well as 41 and 48 mg/kg for ring-immobility and spontaneous locomotor activity, respectively. This profile (high receptor affinity but low in vivo potency) would normally be suggestive of a compound with antagonist properties (at least for immobility and activity measures). It is unclear why these acetylenic analogs were so potent in vitro, while only one (11b) exhibited the degree of in vivo potency anticipated based upon comparison to values for delta 9-THC. It is possible these side chain modifications do not interfere with receptor recognition, but limit receptor activation or second messenger signal transduction. Regardless, it is clear these novel analogs provide a basis for the further exploration of the cannabinoid receptor pharmacophore.
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PMID:A novel class of potent tetrahydrocannabinols (THCS): 2'-yne-delta 8- and delta 9-THCS. 777 26

Anandamide (arachidonylethanolamide), a putative endogenous ligand for the cannabinoid receptor, produces a tetrad of behavioral effects in mice characteristic of psychoactive cannabinoids including catalepsy, antinociception, hypothermia, and hypomobility. The present study examined the discriminative stimulus effects of anandamide in rats trained to discriminate delta 9-tetrahydrocannabinol or the potent cannabinoid receptor ligand CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol)] from vehicle. Intraperitoneal injections of anandamide substituted for delta 9-tetrahydrocannabinol and for CP 55,940; however, unlike substitution dose-effect curves with the training drugs, anandamide substitution occurred at a single dose (30 or 45 mg/kg) and was accompanied by severe decreases in response rates. The results of the present study suggest that, although systemic anandamide administration may have cannabimimetic effects similar to those of delta 9-tetrahydrocannabinol and CP 55,940, some differences in the behavioral effects of anandamide and other psychoactive cannabinoids also are apparent.
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PMID:Discriminative stimulus effects of anandamide in rats. 778 95

In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 and WIN 55,212. The tolerance induced by repetitive administration of CP 55,940 was substantial. The ED50 for CP 55,940 was shifted 102 fold for spontaneous activity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tolerance to delta 9-THC and WIN 55,212 was observed in CP 55,940 chronically treated mice. These findings indicate that cross-tolerance develops between delta 9-THC, CP 55,940 and WIN 55,212 and that these agents have some actions in common. However, quantitative differences in their development of cross-tolerance suggests that all of their actions may not be identical.
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PMID:Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212. 799 50

Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas deferens. The lead analog was also tested for its potency in vivo. Of the analogs tested, (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide [(R)-methanandamide] exhibited the highest affinity for the cannabinoid receptor with a Ki of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (Ki = 78 +/- 2 nM). Moreover, determination of the cannabinoid binding affinity in the presence and absence of the protease inhibitor phenylmethanesulfonyl fluoride (PMSF) revealed that (R)-methanandamide possesses a remarkable stability to aminopeptidase hydrolysis. Pharmacological studies on mouse isolated vasa deferentia demonstrated that all four analogs produce concentration-related inhibition of the twitch response and the order of potency is the same as the rank order of the affinities of these agonists for cannabinoid binding sites. Furthermore, experiments with mice have demonstrated that (R)-methanandamide also possesses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.
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PMID:(R)-methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability. 802 30

The arachidonic acid derivative anandamide (arachidonylethanolamide) has been isolated from porcine brain and has been shown to bind competitively to the cannabinoid receptor. Although the pharmacological activity of this compound has not yet been fully determined, preliminary data suggest that it produces several effects similar ot the cannabinoids. In the present experiments anandamide produced effects similar to those of delta 9-tetrahydrocannabinol, including antinociception (as determined in a latency to tail-flick evaluation), hypothermia, hypomotility and catalepsy in mice after i.v., i.t. and i.p. administration. In general, the effects of anandamide occurred with a rapid onset, but with a rather short duration of action. Prominent antinociceptive effects (> 80% maximal possible effect) were measured immediately after i.v. and i.t. administration. Anandamide produced significant decreases in rectal temperature (2-4 degrees C) after either i.v. or i.t. injection. Maximal effects on motor activity (approximately 85% inhibition) were observed immediately after i.v. and i.p. administration and 10 min after i.t. administration. Maximum immobility observed after i.v. administration was over 80%, yet that produced after i.p. and i.t. administration was too small (< or = 20%) to be considered pharmacologically relevant. Anandamide was less potent (1.3 to 18 times) than delta 9-tetrahydrocannabinol in all behavioral assays. Pretreatment with nor-binaltorphimine, a kappa opioid antagonist which blocks i.t. delta 9-tetrahydrocannabinol-induced antinociception, failed to alter antinociception after i.t. anandamide administration. Binding studies demonstrating that anandamide displaces [3H]CP-55,940 from rat whole brain P2 membrane preparations with a KD of 101 +/- 15 nM. These findings demonstrate that anandamide produces effects in a tetrad of tests used to predict cannabimimetic activity and supports the contention of its role as an endogenous cannabinoid ligand. However, there appear to be distinct differences between anandamide and the cannabinoids with regard to their antinociceptive properties, and other properties vary as a function of route of administration.
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PMID:The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. 803 18

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.
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PMID:Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. 838 16

Although a receptor exists for cannabinoid drugs, it is uncertain which pharmacological actions this receptor mediates. This structure-activity relationship investigation was initiated to determine which effects might correspond to binding affinity for the cannabinoid receptor, as well as to explore the binding requirements of this site. The ability of nearly 60 cannabinoids to displace [3H]CP-55,940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-[3-hydroxy propyl] cyclohexan-1-ol] was determined before establishing correlations between receptor affinity and in vivo pharmacological potency. Analysis of [3H]CP-55,940 binding indicated a Hill coefficient of 0.97, a Bmax of 499 pM (3.3 pmol/mg of protein) and an apparent Kd of 924 pM. Closer inspection indicated the binding assay exhibited "zone B" characteristics, and use of correction equations indicated a true Kd for CP-55,940 of 675 pM. The structure-activity relationship indicated the importance of side chain structure to high-affinity binding, with the most potent analogs (K1 < 10 nM) possessing either a dimethylheptyl side-chain, a similarly complex branched side chain or a halogen substituent at the 5' position. Comparative analysis of K1 values to in vivo potency in a mouse model indicated a high degree of correlation between parameters for the depression of spontaneous locomotor activity (r = 0.91) and for the production of antinociception (r = 0.90), hypothermia (r = 0.89) and catalepsy (r = 0.85). Similarly high correlations were demonstrated between binding affinity and in vivo potency in both the rat drug discrimination model (r = 0.81) and for psychotomimetic activity in humans (r = 0.88).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. 847 8


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