Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cyclohexanols”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 739 records · Page 41Linked to original sources
PubMed1993

In vitro reinforcement of hippocampal bursting by the cannabinoid receptor agonist (-)-CP-55,940.

Involvement of cannabinoid receptors in behavioral reinforcement is suggested by widespread human use of marihuana, although animal tests of cannabinoid reinforcement have produced mixed results. Cannabinoid receptors are found in high density in rat hippocampus and other brain areas. Using the hippocampal-slice preparation, we attempted to demonstrate in vitro reinforcement of CA1 bursting with local micropressure applications of the high-affinity synthetic cannabinoid receptor agonist (-)-CP-55,940. Approximately 60% of the tested neurons showed increased burst activity after a series of brief, burst-contingent applications of (-)-CP-55,940 at pipette concentrations of 5 and 10 microM. Identical microinjections of (-)-CP-55,940 administered independently of cellular activity did not increase and usually suppressed hippocampal bursting. Since general stimulation of CA1 activity by (-)-CP-55,940 can thus be ruled out, we conclude that burst-contingent applications of a cannabinoid receptor agonist can reinforce hippocampal firing in vitro.

Action Potentials↗
PubMed1993

Antinociceptive actions of cannabinoids following intraventricular administration in rats.

Intraventricular administration of 5 or 20 micrograms of the cannabinoids WIN55,212-2 and CP-55,940 markedly reduced rat's responses to noxious thermal stimuli in the tail-flick test; no significant effect was found at 1 micrograms. The dose-response curves were steep and monotonic, the onset was rapid, and the effect lasted about an hour at the highest dose. In contrast to their antinociceptive actions, WIN55,212-2 and CP-55,940 failed to alter the latency of righting reflexes at the highest dose, suggesting that motor impairment did not cause the decreased responsiveness to the thermal stimulus. Finally, an assessment of the biodistribution of intraventricularly administered [3H]WIN55,212-2 in brain and spinal cord at the time of maximal antinociception revealed that the drug was confined to the brain. The levels of [3H]WIN55,212-2 found in S3-S4, the location of the spinal mechanisms for tail-flick, were below the limit of detectability. Together, these findings provide direct evidence that the antinociceptive effects of cannabinoids are mediated, at least in part, by their actions in the brain.

Analgesics↗
PubMed1995

The cannabinoid agonists WIN 55,212-2 and CP 55,940 attenuate rotational behavior induced by a dopamine D1 but not a D2 agonist in rats with unilateral lesions of the nigrostriatal pathway.

The effect of cannabinoid receptor stimulation on rotational behavior induced by a dopamine D1 and a D2 agonist was studied in rats with unilateral 6-hydroxydopamine-induced lesions of the dopaminergic nigrostriatal pathway. The cannabinoid agonists WIN 55,212-2 (2.5 mg/kg) and CP 55,940 (0.1 mg/kg) both markedly attenuated contralateral rotation induced by the D1 agonist SKF 38393 (1.5 mg/kg). In contrast, WIN 55,212-2 and CP 55,940 did not alter rotation elicited by the D2 agonist quinpirole (0.1 mg/kg). Doses of WIN 55,212-2 and CP 55,940 that attenuated D1-mediated rotation did not produce catalepsy in intact rats or in rats with 6-hydroxydopamine-induced lesions, indicating that the reduction in rotation produced by the cannabinoids was not due to a generalized motor impairment. In addition, the effective dose of WIN 55,212-2, but not CP 55,940, produced only a slight increase in ipsilateral rotation when administered alone, making it improbable that this ipsilateral tendency accounts for the reduction in D1-mediated contralateral rotation. These results suggest a preferential interaction between cannabinoid receptor stimulation and dopamine D1 receptor-mediated behavior.

Animals↗
PubMed1996

Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice.

The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanation for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice.

Adenylyl Cyclase Inhibitors↗
PubMed1996

Local pressure application of cannabinoid agonists increases spontaneous activity of rat substantia nigra pars reticulata neurons without affecting response to iontophoretically-applied GABA.

This study tested the hypothesis that cannabinoid agonists, applied locally into the pars reticulata of substantia nigra (SNpr), could modulate striatonigral transmission, without affecting the response of SNpr neurons to iontophoretically-applied GABA. Multibarreled glass capillary electrode assemblies were used for extracellular recording of the spontaneous electrical activity of single SNpr cells in anesthetized rats. Local pressure ejection of the cannabinoid agonists Win 55212-2 (WIN2) and CP 55940 increased SNpr spontaneous firing rate by 13-46%, similar to the effects of systemic injections. Neither WIN2 nor CP 55940 had an effect on the slowing of SNpr neuron activity in response to iontophoretic GABA. Local pressure application of Win 55212-3 (the much less active enantiomer of WIN2) produced an insignificant decrease in SNpr firing rate. Similarly, locally applied vehicle (45% 2-hydroxypropyl-beta-cyclodextrin) produced insignificant decreases in SNpr firing. A second application of cannabinoid agonist produced a much smaller effect, suggesting desensitization. Increasing the interval between CP 55940 applications to 45 min showed recovery of sensitivity to the agonist. Local application of the cannabinoid antagonist, SR 141716A, significantly decreased spontaneous cell firing by 34%. CP 55940, when given immediately following or concurrently with the antagonist application failed to produce the expected increase in discharge rate over baseline. A second application of CP 55940 45 min later produced a 26% increase in firing rate. Bicuculline methiodide (BMI) was applied locally causing a significant increase in SNpr cell firing. CP 55940, when locally administered concurrently with bicuculline methiodide, had no further effect on the firing rate of the cell. Based on the reported presynaptic localization of cannabinoid receptors in SNpr, these findings suggest that cannabinoids act within the SNpr to modulate striatonigral neurotransmission presynaptically. The effect of SR 141716A suggests that an endogenous cannabinoid may mediate striato-nigral transmission.

Action Potentials↗
PubMed1990

A general approach to carbocyclic sugar analogs: preparation of a carbocyclic analog of beta-D-fructofuranose.

The development and execution of the first examples of a new and general approach to carbocyclic analogs of carbohydrates ("pseudo-sugars") is presented. Complete experimental details for the preparation of the carbocyclic analog of beta-D-fructofuranose 6-phosphate are described for the first time. In the conclusion, the success of the synthetic strategy is analyzed and an approach to retrosynthetic analysis based on "unitive synthons" is offered for consideration.

Carbohydrates↗
PubMed1995

Synthesis of 1D-(1,3,5/2,4)-4-acetamido-5-amino-1,2,3-cyclohexanetriol and its incorporation into a pseudo-disaccharide.

The synthesis of the title compound and 1D-(1,3,5/2,4)-4-acetamido-5-amino-3-O-(beta-D-glucopyranosyluronic acid)- 1,2,3-cyclohexanetriol [sequence: see text] is described. Starting from methyl 2-acetamido-2-deoxy-alpha-D-glucopyranoside 2L-(2,4,5/3)-4-acetamido-3-benzoyloxy-2-benzyloxy-5- hydroxycyclohexanone [sequence: see text] was prepared via a series of transformations including the regioselective ring opening of the benzylidene acetal and the mercury(II)-catalyzed carbocyclic ring closure reaction of 5-enopyranoside. Stereoselective reduction of ketone 11 with NaBH(OAc)3 gave 1D-(1,2,4/3,5)-2-acetamido-3-O-benzoyl-4-O-benzyl-1,3,4,5- cyclohexanetetrol [sequence: see text] (88%), which was then converted into 1D-(1,3,5/2,4)-4-acetamido-5-azido-3-O-benzoyl-2-O- benzyl-1-O-pivaloyl-1,2,3-cyclohexanetriol [sequence: see text] through selective 5-OH protection, 1-O-mesylation, and subsequent azide displacement. Saponification and hydrogenation of this gave the title compound. Selective O-debenzoylation with 1.1 equiv of K2CO3 in MeOH gave 1D-(1,3,5/2,4)-4-acetamido-5-azido-2-O-benzyl-1-O- pivaloyl-1,2,3-cyclohexanetriol [sequence: see text] (73%). Glycosylation of this compound with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide) uronate in Ch2Cl2, using silver triflate as the promoter, afforded 1D-(1,3,5/2,4)-4-acetamido-5-azido-2-O-benzyl-3-O-(methyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosyluronate)-1-O- pivaloyl-1,2,3-cyclohexanetriol [sequence: see text] and subsequent hydrogenation of this compound gave the basic pseudo-disaccharide.

Carbohydrate Sequence↗
PubMed1985

DMI, Wy-45,030, Wy-45,881 and ciramadol inhibit locus coeruleus neuronal activity.

Wy-45,030 and Wy-45,881 block the uptake of norepinephrine and serotonin in rat brain synaptosomal preparations and share several in vivo and in vitro effects with known tricyclic antidepressants. To further characterize their activity, these compounds were compared to desipramine and ciramadol in electrophysiological studies of their acute effects on noradrenergic neuronal activity. All four compounds inhibited locus coeruleus neuronal activity with a rank order of potency of desipramine greater than Wy-45,881 greater than Wy-45,030 greater than ciramadol. Administration of the alpha-adrenergic blocking drug, piperoxane, increased locus coeruleus firing rate after desipramine, Wy-45,030 and Wy-45-881. Pretreatment with naloxone prevented the reduction in locus coeruleus impulse flow observed after ciramadol administration but had no effect on the inhibition produced by Wy-45,030. Wy-45,030 and Wy-45,881, like classical antidepressants, appear to inhibit locus coeruleus neuronal firing by potentiating neuroinhibitory transmission of locus coeruleus neurons by blocking the uptake of norepinephrine into presynaptic terminals.

Animals↗
PubMed1987

Effects of tramadol on motor and sensory responses of the spinal nociceptive system in the rat.

The analgesic agent, tramadol, was tested on motor and sensory responses of the nociceptive system in rats. The tail-flick response to radiant heat was dose dependently depressed by tramadol (1-10 mg/kg i.p.), and the antinociceptive effect of the drug was reduced by naloxone in the same range of doses that antagonized the effect of morphine. Tramadol (100 micrograms) microinjected into the periaqueductal grey (PAG) prolonged the tail-flick latency and this effect was abolished by naloxone (0.2 mg/kg i.p.). Aminophylline (25 mg/kg i.p.) did not prevent the antinociceptive effect of tramadol (5 mg/kg i.p.). Tramadol (20 and 40 mg/kg injected i.v.; 100 and 200 micrograms injected intrathecally (i.t.); 100 micrograms injected into the PAG) depressed both the spontaneous activity in ascending axons and their activity due to stimulation of afferent C fibres and co-activation from afferent A delta fibres in the sural nerve. Naloxone injected i.v. at a dose (0.2 mg/kg) that had proven fully effective against the effects of morphine antagonized only the effect on spontaneous activity caused by i.v. injection of tramadol. A high dose of naloxone (1 mg/kg i.v.) not only abolished the depression of spontaneous activity caused by an i.t. injection of tramadol (200 micrograms) but also significantly reduced (but did not abolish) the activity in ascending axons evoked from afferent C fibres while the depression of co-activation from afferent A delta fibres remained unchanged. Aminophylline (50 micrograms i.t.) failed to abolish the depression by tramadol of ascending nociceptive activity. The activity elicited in ascending axons by stimulation of afferent A beta fibres was not changed by i.t. injection of tramadol (200 micrograms), which was evidence that the antinociceptive effect of tramadol is not due to a local anaesthetic action. It is concluded that tramadol produces its antinociceptive and analgesic effects through spinal and supraspinal sites of action. Since the effects of tramadol and morphine differ in some respects, it must be assumed that they are due to binding to different opiate receptors or that some of the effects of tramadol are not mediated by opiate receptors alone.

Animals↗
PubMed1995

Effect of phenylmethylsulphonyl fluoride on the potency of anandamide as an inhibitor of electrically evoked contractions in two isolated tissue preparations.

The endogenous cannabinoid receptor ligand, anandamide, produced a concentration related inhibition of electrically evoked contractions of the guinea-pig myenteric plexus preparation. Its potency was markedly enhanced by phenylmethylsulphonyl fluoride (2.0-200 microM) which presumably acts by inhibiting the hydrolysis of anandamide in this preparation. The degree of this potentiation increased with the concentration of phenylmethylsulphonyl fluoride used. The methyl analogue of anandamide, R-(+)-arachidonyl-1'-hydroxy-2'-propylamide, also inhibited contractions of the guinea-pig myenteric plexus preparation. The potency of this compound was much less affected by phenylmethylsulphonyl fluoride than was the potency of anandamide, confirming its greater resistance to hydrolysis. Phenylmethylsulphonyl fluoride did not alter the inhibitory potency of the cannabinoid, CP 55,940 ((-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4- [3-hydroxypropyl]cyclohexan-1-ol), which is not an amidase substrate. Nor did phenylmethylsulphonyl fluoride affect the ability of anandamide to inhibit electrically evoked contractions of the mouse vas deferens, suggesting that anandamide does not undergo hydrolysis in this tissue.

Analgesics↗
PubMed1995

A study of prostacyclin mimetics distinguishes neuronal from neutrophil IP receptors.

The prostacyclin mimetics BMY 45778 (3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid), BMY 42393 (2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid) and EP 185 (rac 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-(p-methoxyphenyl- phenyl-methylazino)-bicyclo[2.2.2]oct-2-ene) inhibited rat neutrophil aggregation stimulated by N-formyl-methionyl-leucyl-phenylalanine (IC50 = 20, 462, and 1195 nM respectively). In contrast only BMY 45778 (1-10 microM) produced any significant inhibition (10-20%) of the spontaneous activity of rat colon. BMY 45778 (10 microM) also attenuated the inhibitory effect of the prostacyclin analogue cicaprost on rat colon, whereas BMY 42393 and EP 185 did not. BMY 45778 appears to be a low affinity partial agonist at prostacyclin receptors on rat colon and its low potency in rat colon compared with rat neutrophils suggests the presence of a different prostacyclin receptor located on enteric neurones.

Acetates↗
PubMed1995

Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens.

The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoy)indole, produced a dose-related inhibition of electrically evoked contractions of the mouse vas deferens, with IC50 values of 2.56 nM, 3.38 nM and 639 nM respectively. Kd values of the selective CB1 cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride], determined in the vas deferens from experiments with these compounds are 1.34 nM, 3.86 nM and 8.06 nM respectively, indicating their susceptibility to antagonism by SR141716A is similar to that of their parent compound, the CB1 cannabinoid receptor agonist WIN 55,212-2 ¿(R)-(+)-[2,3-dihydro-5-methyl-3-[4-methylino)methyl]pyrrolo-[1,2, 3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone}. SR141716A (100 nM) had no effect on the actions of two non-cannabinoid receptor agonists, morphine and clonidine. These results provide strong support for the hypothesis that 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole are cannabinoid receptor agonists and confirm that the WIN 55,212-2 molecule can be modified considerably without detectable loss of cannabinoid activity.

Animals↗
PubMed1996

Effects of cannabinoid receptor stimulation and blockade on catalepsy produced by dopamine receptor antagonists.

The ability of cannabinoid receptor stimulation or blockade to alter catalepsy produced by dopamine D1 and D2 receptor antagonists was studied in rats. The cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamidehydrochloride) (0.5 and 2.5 mg/kg) reduced catalepsy elicited by the cannabinoid receptor agonist CP 55,940 (1 alpha,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl ) cyclohexyl-phenol) (0.5 mg/kg). However, SR 141716A (0.5 and 2.5 mg/kg) did not decrease catalepsy produced by the dopamine D1 receptor antagonist SCH 23390 (R-(+)-7chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1-H-3-benzazepine) (0.5 mg/kg) or the dopamine D2 receptor antagonist raclopride (S(-)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl)-methyl-6-methoxysalicylami de) (2.5 mg/kg), suggesting that, under these conditions, endogenous cannabinoid ligands do not modulate the cataleptic effects of dopamine D1 or D2 receptor antagonists. In contrast, CP 55,940 (0.025 and 0.1 mg/kg), at doses which do not produce catalepsy when administered alone, enhanced catalepsy produced by SCH 23390 and raclopride. These results suggest that stimulation, but not blockade, of brain cannabinoid receptors modifies catalepsy behavior produced by selective dopamine D1 and D2 receptor blockade.

Animals↗
PubMed1996

Further evidence for the presence of cannabinoid CB1 receptors in mouse vas deferens.

Our results provide further evidence for the hypothesis that the mouse vas deferens contains cannabinoid CB1 receptors. Thus we found that in the presence of forskolin, the cannabinoid receptor agonist, CP 55,940 ((-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-(3- hydroxypropyl)cyclohexan-1-ol) produced a concentration related inhibition of cyclic AMP production by the vas deferens (EC50 = 6.0 nM). At 100 nM, SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamide hydrochloride) attenuated this effect of CP 55,940, producing a parallel rightward shift in its log concentration-response curve (Kd = 4.3 nM). We also found that cyclic AMP production was inhibited by (-)-11-hydroxy-1',1'-dimethylheptyl-delta 8- tetrahydrocannabinol but not by the (+) enantiomer.

Animals↗
PubMed1990

The morphogenesis of cyclohexylamine-induced testicular atrophy in the rat: in vivo and in vitro studies.

Male Wistar strain rats were fed a diet providing an intake of 0 or 400 mg cyclohexylamine (CHA)/kg body weight/day for 1, 3, 7, 9, or 13 weeks. At the end of the appropriate feeding period the rats were perfused-fixed with Karnovsky's fixative. The weights of the fixed testes were recorded and the testes, epididymides, and spermatic cord were sampled and processed into methacrylate resin. Histopathological examination of the testes showed changes after 3 weeks of CHA administration. The most frequent and consistent lesion consisted of a focal, basal vacuolation of the Sertoli cell cytoplasm associated with the local loss of spermatocytes and spermatogonia. After a 7-week administration, the Sertoli cell vacuolation was extensive, while the germ cell population showed mild to moderate degeneration and depletion. After longer periods of treatment the lesion was more severe and affected a greater number of tubules leading to general disruption of the germinal epithelium. Cocultures of Sertoli and germ cells were prepared from the testes of Wistar strain rats and exposed to (CHA) or its metabolite 4-aminocyclohexanol (4ACH) at concentrations ranging from 0.1 to 10 mM for periods of 24-72 hr. The cultures were fixed, stained, and examined by light microscopy. Cultures exposed to CHA or 4ACH showed morphological changes comparable with those seen in vivo. Sertoli cell vacuolation was the earliest change with progressive germ cell degeneration and exfoliation from the Sertoli cell monolayer. At equimolar concentrations, CHA produced more marked changes than 4ACH. These results suggest that CHA itself acts directly on the testis and that its primary cellular target is the Sertoli cell.

Aging↗