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At least 757 records · Page 42Linked to original sources
PubMed1991

The effects of substrates, products and other ligands on the susceptibility of inositol monophosphatase to proteolysis by endoprotease lys-C.

Inositol monophosphatase is cleaved by endoprotease lys-C at a single site (Lys36-Ser37). The rate of proteolysis is greatly reduced in the presence of substrate (D,L-Ins(1)P) and Mg2+, and less so in the presence of Pi and Mg2+, consistent with protection of the susceptible bond in the E-P or E-Pi states of the enzyme. Potentiation by Li+ of the protection afforded by a substrate analogue, 1S-phosphoryloxy-2R,4S-dihydroxycyclohexane, and Mg2+ supports the idea that Li+ binds to the E-P state.

Cyclohexanols↗
PubMed1994

SR141716A, a potent and selective antagonist of the brain cannabinoid receptor.

SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the peripheral cannabinoid receptor. In vitro, SR141716A antagonises the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes. After intraperitoneal or oral administration SR141716A antagonises classical pharmacological and behavioural effects of cannabinoid receptor agonists. This compound should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.

Animals↗
PubMed1995

Cannabinoids enhance human B-cell growth at low nanomolar concentrations.

This study examined the effect of cannabinoid ligands on human tonsillar B-cells activated either through cross-linking of surface immunoglobulins or ligation of the CD40 antigen. The two synthetic cannabinoids, CP55,940 and WIN55212-2, as well as delta 9-tetrahydrocannabinol (THC), the psychoactive component of marijuana, caused a dose-dependent increase of B-cell proliferation and displayed EC50 at low nanomolar concentrations. This cannabinoid-induced enhancing activity was inhibited by pertussis toxin which suggested a G-protein-coupled receptor process. In addition, the absence of antagonistic effect of SR141716A, a specific CB1 receptor antagonist, together with the demonstration that human B-cells displayed large amount of CB2 receptor mRNAs, led us to assume that the growth enhancing activity observed on B-cells at very low concentrations of cannabinoids could be mediated through the CB2 receptor.

Antigens, CD↗
PubMed1994

Cannabinoid receptors in rat brain areas: sexual differences, fluctuations during estrous cycle and changes after gonadectomy and sex steroid replacement.

Cannabinoid effects on brain dopaminergic activity vary as a function of gonadal status. In this work, we examined whether these variations might be due to sex steroid-dependent differences in brain cannabinoid receptors (CNr). Four experiments were done: (i) male versus females; (ii) females at each stage of the ovarian cycle; (iii) estradiol (E2) and/or progesterone (P)-replaced ovariectomized (OVX) females; and (iv) testosterone (T)-replaced orchidectomized males. The density of CNr in the medial basal hypothalamus fluctuated in females during the estrous cycle. The density was higher in diestrus and decreased in estrus. This parameter did not change after ovariectomy and E2 replacement. However, P increased the density of CNr when administered to OVX rats acutely treated with E2, but not administered alone or after chronic E2 treatment. In the striatum, the affinity of CNr was slightly higher in males than females, with no changes in density. Ovariectomy increased the affinity of CNr, which normalized only after administration of acute E2. Interestingly, the high affinity values observed in this area after P alone or combined with E2, corresponded to low densities as compared with intact females. In the limbic forebrain, the affinity for the cannabinoid ligand was also higher in males than females with no changes in density. Affinity was also higher in diestrus and lower in estrus, whereas density was unchanged. Ovariectomy decreased CNr density. A normal situation was found after administration of acute E2 or P alone, whereas chronic E2 markedly increased the density of CNr as compared with both intact and OVX females. Interestingly, this latter increase was prevented by coadministration of P. Orchidectomy did not affect CNr density, but administration of T produced a marked decrease. In the mesencephalon, the density and affinity of CNr was higher in males than females. Administration of P to OVX rats produced opposite effects, increasing the density when administered alone and decreasing it when administered to acute E2-replaced OVX rats. In summary, these results reveal the existence of subtle, sometimes more pronounced, sex dimorphisms, fluctuations along the ovarian cycle and changes after gonadectomy and sex steroid replacement in CNr density and affinity in certain brain areas. This supports the hypothesis of possible sex steroid-dependent differences in the sensitivity of certain neuronal processes to cannabinoid treatment.

Animals↗
PubMed1995

AM630, a competitive cannabinoid receptor antagonist.

AM630 (iodopravadoline), a novel aminoalkylindole, has been found to attenuate the ability of a number of cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens. It did not block the inhibitory effects of morphine or clonidine on the twitch response. AM630 behaved as a competitive antagonist of CP 55,940, WIN 55,212-2, anandamide and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (AM356), producing rightward shifts in the log concentration response curves of these cannabinoid receptor agonists that were concentration-dependent, essentially parallel and not accompanied by any decrease in the size of maximal response. AM630 also produced concentration-dependent, parallel rightward shifts in the log concentration-response curve of delta 9-THC. However, these shifts were accompanied by a decrease in the maximal response. AM630 was markedly more potent as an antagonist of delta 9-THC and CP 55,940 (Kd = 14.0 and 17.3 nM respectively) than as an antagonist of WIN 55,212-2, AM356 or anandamide (Kd = 36.5, 85.9 and 278.8 nM respectively). These differences in dissociation constant imply that the mouse vas deferens may contain more than one type of cannabinoid receptor. The data also indicate that the receptors for which AM630 has the highest affinity may not be CB1 cannabinoid receptors as the CB1 selective antagonist, SR141716A, is known to be equally potent in attenuating the inhibitory effects of CP 55,940 and anandamide on the twitch response of the mouse vas deferens.

Animals↗
PubMed1995

A novel electrophilic high affinity irreversible probe for the cannabinoid receptor.

In order to explore the structural requirements for cannabinoid activity we have been involved in the design and synthesis of stereochemically defined high affinity probes for the cannabinoid receptor. This effort has involved the development of irreversible ligands which will allow us to obtain detailed information on the cannabinoid receptor active site(s). The irreversible ligands, which incorporate highly reactive functional groups in a strategic position of the ligand, may form covalent bonds with amino acid residues at the receptor active site or in the neighborhood of this site. We shall discuss the biochemical properties of one of these probes, which incorporates the electrophilic isothiocyanate group into the structure of the highly potent cannabinoid agonist (-)-1',1'-dimethylheptyl-delta 8-THC. This ligand, (-)-7'-isothiocyanato-1',1'-dimethylheptyl-delta 8-THC (7'-NCS-DMH-delta 8-THC), was evaluated for its affinity for cannabinoid binding sites using rat forebrain membrane preparations and found to have an apparent IC50 value of 660 pM. Incubation of the membrane preparation with a ligand concentration of five times the apparent IC50 resulted in the irreversible occupation of nearly all of the receptor specific binding sites.

Affinity Labels↗
PubMed1995

Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain.

We have synthesized a range of hybrid classical/non-classical cannabinoids (CC/NCCs) combining the hexahydrocannabinol dibenzopyran structure with the hydroxyalkyl chain found in CP-55940, in order to investigate the role of the hydroxyalkyl pharmacophore in cannabimimetic activity. This was achieved by synthesizing CC analogs in which the 6 alpha- and 6 beta-methyl groups were modified to the corresponding hydroxyethyl groups. Our binding data indicated that beta position was the preferred orientation for the hydroxyalkyl moiety, affinity for the CB1 receptor being 20-fold greater for the 6 beta-hydroxyethyl than the corresponding 6 alpha-analog. Further studies using 6 beta-hydroxyalkyldibenzopyran analogs varying the southern aliphatic chain length from 6 beta-hydroxymethyl to 6 beta-hydroxyethyl to 6 beta-hydroxypropyl demonstrated little potency change with chain length. Therefore, we concluded that whilst the hydroxyalkyl pharmacophore was strongly affected by its configuration relative to the dibenzopyran ring, the chain length of the hydroxyalkyl moiety (up to the n = 3 homolog) was not critical.

Animals↗
PubMed1995

Variation of the alkyl side chain in delta 8-THC.

The synthesis of (2'RS)-2'-methyl-, (3'RS)-, (3'S)-3'-methyl-, and 4'-methyl-delta 8-THC has been carried out, and the pharmacology of all four compounds has been investigated. All four compounds showed typical cannabinoid activity both in vitro and in vivo. The 2'-methyl compound is somewhat more active than delta 8-THC, while the 4'-methyl isomer is less active. The 3'-methyl-delta 8-THC has approximately the same activity as the parent cannabinoid.

Analgesics↗
PubMed1995

Pharmacological and behavioral evaluation of alkylated anandamide analogs.

Anandamide (arachidonylethanolamide), isolated from porcine brain, has been shown to bind to the cannabinoid receptor and also to produce cannabimimetic activity in pharmacological assays. This study examined structure-activity relationships in alkylated anandamide analogs. The analogs were evaluated for their ability to displace [3H]CP-55,940 in a filtration binding assay using rat brain membranes in the presence and absence of the enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF). Behavioral activity was assessed by the ability of the analogs to produce hypomotility and antinociception. Methylations at carbons 2 and 1 produced compounds stable in the absence of PMSF with similar affinities and behavioral activity as anandamide. Addition of larger alkyl groups at these positions or nitrogen methylation reduced receptor affinity and behavioral potency. These results indicate that methylations at specific carbons of anandamide confer stability in vitro.

Alkylation↗
PubMed1995

Evaluation of cAMP involvement in cannabinoid-induced antinociception.

It has been proposed that cannabinoids act at a Gi protein-coupled receptor to produce antinociception. One action of Gi-proteins is to decrease intracellular cAMP via inhibition of adenylyl cyclase activity. Although cannabinoid inhibition of forskolin-stimulated adenylyl cyclase is used as a confirmation of functional cannabinoid receptors, it is unknown whether this second messenger system specifically mediates cannabinoid-induced antinociception. This in vivo study was conducted using enantiomeric cAMP analogs, Rp-cAMPS (an antagonist) and Sp-cAMPS (an agonist), and the cAMP agonist Cl-cAMP to test the hypothesis that cannabinoid-induced antinociception is due to decreased adenylyl cyclase activity. None of the cAMP analogs, forskolin, or 1,9-dideoxy-forskolin affected delta 9-THC or CP-55,940-induced antinociception produced by intrathecal (i.t.) or intracerebroventricular (i.c.v.) injections in mice. Experiments were also conducted to investigate whether i.c.v. administration of Sp-cAMPS would block i.c.v. cannabinoid-induced antinociception in rats. Sp-cAMPS failed to block CP-55,940-induced antinociception. However, Sp-cAMPS produced hyper-excitability and reactive behavior indicating that it did elicit a pharmacological effect. Although, adenylyl cyclase may mediate other cannabinoid-induced actions, these results do not support the hypothesis that it is involved in cannabinoid-induced antinociception. Alternatively, other effector systems such as calcium or potassium channels coupled to cannabinoid receptors may mediate cannabinoid-induced antinociception.

Analgesics↗
PubMed1995

An examination of the central sites of action of cannabinoid-induced antinociception in the rat.

Microinjections of low doses of the potent and selective cannabinoids WIN 55,212-2 and CP 55,940 into the lateral ventricle produce long-lasting reduction in sensitivity to noxious thermal stimuli (1). To determine the central distribution of ventricularly administered WIN 55,212-2, we microinjected an analgesic dose of the drug with [3H]WIN 55,212-2. At the peak time of antinociception, the radiolabeled drug was confined to periventricular sites throughout the brain. The contribution of particular periventricular structures to the antinociceptive effect was evaluated using intracerebral microinjection techniques and the tail-flick test. Guide cannulae were implanted above the following periventricular structures: the medial septal area, lateral habenlua, perihypothalamic area, arcuate nucleus of the hypothalamus, dorsal raphe nucleus and the dorsolateral and ventrolateral aspects of the periaqueductal gray. Microinjections of WIN 55,212-2 (5 micrograms/0.5 microliter) into the medial septal area, lateral habenula, perihypothalamic area, arcuate nucleus, and ventrolateral periaqueductal gray did not significantly affect tail-flick latencies. By contrast, microinjections of WIN 55,212-2 into the dorsolateral periaqueductal gray and the dorsal raphe significantly elevated tail-flick latencies. The results of this study indicate that at least two periventricular structures within the brain are involved in cannabinoid antinociception.

Analgesics↗
PubMed1990

Stereochemical effects of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor.

The recent preparation of the enantiomers of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (THC-DMH), recrystallized to absolute enantiomeric purity, has made it possible to examine the requirement for stereospecificity for the interaction of this component with the cannabinoid receptor, defined by the binding of [3H]CP-55,940 and the adenylate cyclase enzyme. The enantiomer (-)11-OH-delta 8-THC-DMH exhibited a fully efficacious and potent (IC50 = 1.8 nM) inhibition of the accumulation of cAMP in intact N18TG2 cells. The (-)enantiomer was as efficacious and potent (Kinh = 7.2 nM) as desacetyllevonantradol in inhibiting adenylate cyclase activity in membrane preparations. The (-)enantiomer was able to compete fully for the specific binding of [3H]CP-55,940 to membranes from the brain of the rat in homologous displacement studies (Ki = 234 pM). The potency ratios exhibited by the (-) to (+)enantiomers of 11-OH-delta 8-THC-DMH exceeded 1000 for each of these activities.

Adenylyl Cyclase Inhibitors↗
PubMed1993

Venlafaxine exhibits pre-clinical antidepressant activity in the resident-intruder social interaction paradigm.

Venlafaxine, a novel 2-phenyl-2-(1-hydroxycycloalkyl) ethylamine, is a potent inhibitor of 5-hydroxytryptamine and noradrenaline reuptake and exhibits a profile of activity in pre-clinical in vitro biochemical studies predictive of antidepressant activity. The studies described here examined the effects of acute and chronic treatment with venlafaxine on the behaviour of resident rats confronted with an unfamiliar, non-treated, intruder conspecific. Ethological analysis of the social encounters revealed that acute, subcutaneous, treatment with venlafaxine, 20-180 mumol kg-1, induced a selective, dose-related, reduction in aggressive behaviour (ID50 = 24.87 mumol kg-1) concomitant with increased flight behaviour. In contrast, chronic treatment with venlafaxine, 20 mumol kg-1 day-1, via subcutaneously-implanted osmotic mini-pumps, induced a marked elevation in aggressive behaviour concomitant with reduced flight behaviour. These diametrically opposite effects of acute and chronic venlafaxine treatment on the agonistic behaviour of resident rats are consistent with the behavioural effects of similar treatment regimes previously identified for a range of antidepressant drugs that differ widely in their acute pharmacology. These data strongly support the potential antidepressant activity of venlafaxine and are consistent with the results of recent clinical trials which demonstrate that venlafaxine exhibits significant antidepressant activity.

Aggression↗
PubMed1995

Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats.

CP 55,940 is a potent synthetic bicyclic cannabinoid analog that has been used in a number of studies as a radioligand for the cannabinoid receptor. This compound shares behavioral and biochemical properties with naturally occurring cannabinoids such as delta 9-THC. The purpose of the present study was 3-fold: to establish the ability of CP 55,940 to serve as a discriminative stimulus, to determine whether this discriminative stimulus is identical to that of delta 9-THC, and to examine whether a newly developed cannabinoid antagonist, SR141716A, would antagonize the discriminative stimulus effects of CP 55,940. Rats were trained to discriminate 0.1 mg/kg CP 55,940 from vehicle in standard 2-lever operant conditioning chambers. CP 55,940 produced dose-dependent generalization from the training dose in dose-effect determinations conducted before and after testing with other drugs. The effects of the training dose of CP 55,940 were dose-dependently antagonized by co-administration of SR141716A. Results of substitution tests showed that delta 9-THC, WIN 55,212-2, and cannabinol substituted completely for CP 55,940 in a dose-dependent manner; however, CP 55,940 was approx 10-fold more potent than any of the other drugs in producing CP 55,940-like discriminative stimulus effects. Several drugs with CNS depressant properties (phencyclidine, haloperidol and diazepam) failed to produce reliable substitution for CP 55,940. These results demonstrate that CP 55,940 has discriminative stimulus effects and that it shares these effects with structurally dissimilar compounds that, like CP 55,940, bind to the cannabinoid receptor. Further, these effects are blocked by SR141716A, a cannabinoid receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1989

Temporal integration and reaction times in human smell.

A model description of intensity perception in human taste and smell developed earlier has now been verified experimentally to determine parameter values for odorants. The final objective is to quantify and understand odour-odour interaction phenomena in e.g., masking, deo-perfumes and flavour enhancement. Five types of olfactometer experiments were carried out, viz. determination of thresholds, determination of reaction times, scaling of perceived intensity after 5 sec stimulation, scaling of perceived intensity of a fixed concentration at variable duration, and measurement of intensity/time relationships. Four subjects were used and the odorants cineole, geraniol and hexane.

Acyclic Monoterpenes↗
PubMed1995

Linalool and cineole type glucosides from Cunila spicata.

The leaves of Cunila spicata yielded a monoterpenetriol and six glycosidic terpenoids derived from linalool, hydroxylated linalool and 1,8-cineole: 3,7-dimethyl-oct-1-ene-3,6,7-triol, linalool-O-beta-D-glucopyranoside, 3,7 dimethyl-octa-1,6-diene-3,8-diol-3-O-beta-D-glucopyranoside as well as 3,7-dimethyl-octa-1,5-diene-3,7-diol-3-O-beta-D-glucopyranoside, 3,7-dimethyl-octa-1,7-diene-3,6-diol-7-O-beta-D-glucopyranoside, 3,7- dimethyl-oct-1-ene-3,6,7-triol-6-O-beta-D-glucopyranoside and (1S,4R,6R)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-O-beta- glucopyranoside. The structures of the glucosides were established by chemical and spectroscopic methods especially high field NMR techniques.

Acyclic Monoterpenes↗