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PubMed2005

The novel GABA adamantane derivative (AdGABA): design, synthesis, and activity relationship with gabapentin.

A facile preparation of 2-aminomethyl-2-tricyclo[3.3.1.1(1,7)]decaneacetic acid hydrochloride 5 (AdGABA) is described. The synthesis of AdGABA involves the hydrogenation of 2-cyano-2-tricyclo[3.3.1.1(1,7)]decaneacetic acid 11, which was synthesized by two different synthetic routes. AdGABA was found to antagonize the pentylenetetrazole (PTZ) and semicarbazide (SCZ) induced tonic convulsions and exhibits analgesic activity in the hot plate test on mice. Although its mechanism of action is quite similar to that proposed previously for gabapentin (interaction with the alpha2delta subunit of the voltage gated Ca2+ channels), further studies were undertaken in order to clarify the precise mechanism of the anticonvulsant and analgesic effects of AdGABA on a molecular level.

Acetates↗
PubMed1988

Effects of antiallergic drugs on bronchial and cutaneous anaphylaxis in Lewis rats.

Effects of antiallergic agents on 2,4-dinitrophenylated Ascaris extract (DNP-As)-induced bronchial asthma were studied in Lewis rats, and compared with those on passive cutaneous anaphylaxis (PCA). Effects of methysergide and chlorpheniramine on the bronchial asthma model were also investigated. Rats were actively sensitized with DNP-As antigen and with killed Bordetella pertussis. After 8 d, asthmatic response was provoked by inhalation of DNP-As. The bronchomotor response was measured with a modified Konzett-Rössler method in diaphragm-sectioned rats. The inhalation of DNP-As caused a marked asthmatic bronchoconstriction without significant effect on systemic blood pressure and heart rate. Disodium cromoglycate (DSCG), 10 mg/kg, i.v., trans-4-guanidinomethylcyclohexanecarboxylic acid p-tert-butylphenyl ester hydrochloride (NCO-650) and tranilast at doses of 30 and 100 mg/kg, intraduodenally, significantly inhibited the asthmatic response. Chlorpheniramine and methysergide at a dose of 1 mg/kg, i.v. also significantly inhibited it. The above doses of NCO-650 and tranilast significantly inhibited 48 h PCA, while DSCG almost abolished the PCA. These results indicate that 1) NCO-650 and tranilast inhibited both the asthmatic response and PCA in almost the same degree, 2) DSCG inhibited PCA much more strongly than asthmatic response, and 3) histamine and 5-hydroxytryptamine may be involved in this asthmatic response.

Anaphylaxis↗
PubMed1998

Isolation of the [3H]gabapentin-binding protein/alpha 2 delta Ca2+ channel subunit from porcine brain: development of a radioligand binding assay for alpha 2 delta subunits using [3H]leucine.

The novel antiepileptic agent gabapentin (Neurontin) binds with high affinity to the alpha 2 delta subunit of a voltage-dependent Ca2+ channel. We report here a simple purification scheme for detergent-solubilized alpha 2 delta subunits from porcine brain. This involves sequential chromatography on Q-Sepharose, Cu(2+)-charged iminodiacetic acid-Sepharose, wheat germ lectin-agarose, and Mono Q. The purified protein was essentially homogeneous by SDS-polyacrylamide gel electrophoresis with a subunit Mr of 145,000. Using [3H] gabapentin as the radiolabeled tracer and (S)-3-isobutyl gamma-aminobutyric acid to define nonspecific binding, the overall purification factor was 2760-fold and the apparent yield 26.6%. We also developed and validated a novel binding assay for alpha 2 delta Ca2+ channel subunits using the ligand pair L-[3H]leucine/L-isoleucine. Even in binding assays of crude brain membrane fractions, [3H]leucine proved to be remarkably stable and specific for the alpha 2 delta Ca2+ channel subunit. [3H]Leucine offers several advantages over custom-labeled [3H]gabapentin: it has a higher specific activity, is relatively inexpensive, and is available from commercial sources.

Acetates↗
PubMed2004

Highly potent PDE4 inhibitors with therapeutic potential.

The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure-activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1975

Effect of triphenylmethane derivatives on cell-free macromolecular synthesis. II. mRNA-ribosome binding.

The specific inhibition by aurintricarboxylic acid (ATA) of mRNA binding to ribosomes was re-examined. Among triphenylmethane compounds, all of which are potent inhibitors for phenylalanyl=tRNA synthetase, ATA is the most potent inhibitor. Two other dyes, Aurine and Azure Blue B, inhibit the reaction, but the concentration for 50% inhibition is far higher than that for ATA. It appears that the presence of the carboxyl group on the skeletal-triphenylmethane structure enhances the inhibition of the mRNA-binding reactionmthis feature is slightly different from that of the phenylalanyl-tRNA synthetase reaction, in which the skeletal structure of the dye itself is essential to its inhibitory action.

Animals↗
PubMed1987

Postembedding immunocytochemical GABA labeling in rat neocortex cultures: applicability in quantitative studies.

The value of gamma-aminobutyric acid (GABA) immunogold labeling in the quantification of nerve endings was studied in dissociated rat neocortex cultures. Adjacent sections were processed in 3 series according to the same staining protocol. Of all nerve ending profiles examined, 20% appeared to be GABA-positive, while 7% could not be classified. In cultures pretreated with gabaculine, GABA-positive endings were labeled more heavily. Cell bodies could always be discriminated as GABA-positive or GABA-negative. Of all neuronal cell profiles, 14% appeared to be GABA-positive. These neurons could also be identified by light microscopy using the peroxidase-anti-peroxidase method.

Animals↗
PubMed1989

Participation of ornithine aminotransferase in the synthesis and catabolism of ornithine in mice. Studies using gabaculine and arginine deprivation.

Gabaculine, a potent suicide inhibitor of ornithine aminotransferase (OAT), at a dose of 50 mg/kg inhibited this enzyme in mouse tissues and dramatically increased tissue ornithine concentrations, whether or not arginine was present in the diet. Thus even under arginine deprivation there is catabolism of ornithine which involves OAT. This was confirmed by administration of [14C]ornithine to arginine-deprived mice. Gabaculine (3-amino-2,3-dihydrobenzoic acid) drastically decreased the release of 14CO2 and increased the radioactivity in the basic amino acids in the tissues. When [1-14C]glutamate was injected into mice deprived of arginine, a significant amount of radioactivity was recovered in tissue ornithine and arginine, and gabaculine decreased this labelling by about two-thirds, indicating that ornithine was synthesized in vivo from glutamate via OAT. In addition, we failed to detect in liver and small intestine alpha-N-acetylornithine, N-acetylglutamate kinase or N-acetylornithine aminotransferase, which are obligatory components of a potential route of ornithine synthesis from N-acetylglutamate. Our results indicate that at least 45 mumol of ornithine was synthesized and catabolized daily via OAT in the mouse deprived of arginine.

Animals↗
PubMed1995

Stereoselective inhibition of muscarinic receptor subtypes by the eight stereoisomers related to rociverine.

The chemical structure corresponding to 1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid 2-(diethylamino)-1-methylethyl ester has the classical profile of ester-type antimuscarinic drugs. The presence of three chiral carbons leads to eight stereoisomers and the substitutions on the cyclohexyl ring generate cis-isomers (1, named rociverine) and trans-isomers (2). The aim of this study was to determine the binding pattern of the eight stereoisomers and two derived compounds, (1S,2S)-1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid 2-(dimethylamino)-1-ethyl ester (3) (1S,2S)-1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid (S)-2-(diethylamino)-1-methylethyl ester methyl iodide (4), at the five cloned muscarinic receptors stably expressed in chinese hamster ovary cells, in order to define how stereochemical modifications could affect the affinity. Our data showed that cis-stereoisomers exhibited higher variations in affinity than trans-stereoisomers. Among the cis-stereoisomers, those with the (1R,2R) configuration showed considerably higher affinities (up to 240-fold) than those with the (1S,2S) configuration. The (1S,2S) configuration was important for binding selectivity; this was confirmed also by the use of the two additional compounds.

Animals↗
PubMed1996

[Gabapentin (Neurontin): a new possibility in the add-on therapy of partial epilepsies].

Gabapentin is a new antiepileptic drug for add-on therapy in patients above the age of 12 years with otherwise refractory partial seizures. Its unknown molecular mode of action is probably related to amino-acid-related binding sites in the brain. There are no hints to toxicologic effects or damage of the hematopoietic system, liver, or kidney in man. With the exception of a rather short elimination half life and dose-limited abortion, the pharmacokinetic data are very favourable. Due to lack of protein binding and metabolization, there are no major interactions with antiepileptic or other drugs. Efficacy has been demonstrated in three multicenter, placebo controlled trials involving a total of 705 patients. Secondarily generalized seizures seem to be the most likely to respond to 900 to 1800 mg/day, followed by complex partial and simple partial seizures. Tolerance is good, and serious side effects have not been observed up to now.

Acetates↗
PubMed1981

Determination of tranexamic acid (AMCA) and fibrin/fibrinogen degradation products in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage.

Six patients with recently ruptured intracranial aneurysms were treated preoperatively with tranexamic acid (AMCA). Two patients received 6 g daily in i.v. infusion, two had 6 g daily by i.v. injection, and two patients were given AMCA 9 g daily by mouth during the first week after bleeding. Serial assays of AMCA and fibrin/fibrinogen degradation products (FDP) in cerebrospinal fluid (CSF) were performed during 6--13 days after the initial subarachnoid haemorrhage (SAH). Judged from the decline in CSF-FDP, an assumed therapeutic level of greater than or equal to 1 mg/l of AMCA in CSF was reached within 24--36 hours after the first dose when the drug was administered intravenously and within 48 hours when the drug was given orally.

Adult↗
PubMed1982

Ultrastructural study of the effects of tranexamic acid and urokinase on metastasis of Lewis lung carcinoma.

Lewis lung carcinoma cells were implanted in the foot-pads of mice and the effects of the plasminogen-plasmin inhibitor tranexamic acid (t-AMCHA) and of the plasminogen activator urokinase on metastasis were examined by electron microscopy. The intravascular tumour cells were not associated with thrombus formation in either control or urokinase-treated mice. Polymerized fibrin deposition around tumour cells and thrombi composed of fibrin and platelets was observed only in the mice given t-AMCHA. This suggests that the inhibition of fibrinolysis by tACC caused fibrin deposition and thrombus formation around intravascular tumour cells, which prevented release of the cells from primary foci to form secondary tumours. On the other hand, fibrinolysis induced by urokinase prevented thrombus formation, and accelerated cell release from primary foci.

Animals↗
PubMed1984

The hemostatic effect of tranexamic acid in conisatio colli uteri.

To evaluate the inhibitory effect of tranexamic acid (AMCA) on increased fibrinolyctical activity in connection with conisatio colli uteri we have carried out a randomized, double-blind study with patients operated upon partly with an open method of operation (80 patients) and partly with modified Sturmdorff sutures (150 patients). In connection with the open method the frequency of late bleeding decreased from 17.5% to 2.5%, which is significant. The corresponding decrease in connection with the other method was from 10.7% to 4.1%. This material was not sufficiently large to verify significance. The side effects of the prophylactic treatment with AMCA were few. The study indicates that AMCA affords good protection against late bleeding in conisatio colli uteri.

Adult↗
PubMed2000

Cypellocarpins A-C, phenol glycosides esterified with oleuropeic acid, from Eucalyptus cypellocarpa.

Three new phenol glycosides acylated with (+)-oleuropeic acid, cypellocarpins A (1), B (2), and C (3), along with seven known compounds, were isolated from the dried leaves of Eucalyptus cypellocarpa. Structures of the new compounds were determined on the basis of spectroscopic methods, including 2D NMR experiments and chemical degradation. These new compounds and a known related glucoside (7) showed potent in vitro antitumor-promoting activity in a short-term bioassay evaluating the inhibitory effect on Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoyl phorbol 13-acetate (TPA). These compounds also suppressed an in vivo two-stage carcinogenesis induced with nitric oxide and TPA on mouse skin.

Animals↗
PubMed2004

Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents.

Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acid-induced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tail-flick and hot plate tests. In models of inflammatory and/or persistent pain, duloxetine, morphine, and ibuprofen produced dose-related decreases in acetic acid-induced writhing in mice. Duloxetine, ibuprofen, and gabapentin also produced dose-dependent reversals of both thermal hyperalgesia and mechanical allodynia produced by carrageenan in rats. In addition, both duloxetine and morphine produced a significant reduction of capsaicin-induced mechanical allodynia in rats. Duloxetine and gabapentin were without substantial effect on the Rotorod test in mice, whereas morphine and ibuprofen produced a significant impairment. Our data indicate that duloxetine may be efficacious in the treatment of persistent and/or inflammatory pain states at doses that have modest or no effect on acute nociception or motor performance.

Adrenergic Uptake Inhibitors↗
PubMed1998

Anticonvulsants for neuropathic pain and detoxification.

It is now well demonstrated that several anticonvulsants have a role in the treatment of neuropathic pain and also in withdrawal from benzodiazepines, sedatives, and perhaps alcohol. Valproic acid, carbamazepine, gabapentin, clonazepam, and lamotrigine are appropriate treatments for neuropathic pain, effective to a degree dependent on the underlying pathophysiology. While less effective than newer agents, there are situations in which phenytoin remains useful. Currently, a limited understanding of both the processes responsible for pain and the specific effects of each agent prevents prediction of individual response to these drugs, often necessitating trials of several drugs before the best one is found. It is interesting that the anticonvulsant drugs most useful for neuropathic pain are the same ones effective in sedative withdrawal, bipolar disorder, and several anxiety disorders. Issues of neural hypersensitivity and kindling, therefore, may prove to be unifying concepts for these conditions.

Acetates↗
PubMed1982

Serotonin and gamma-aminobutyric acid turnover after injection into the median raphe of substance P and D-ala-met-enkephalin amide.

The raphe nuclei [which contain serotonin (5-HT) cell bodies] are also known to contain axons that store substance P, met-enkephalin, and gamma-aminobutyric acid (GABA). We have previously shown that GABA has a tonic inhibitory action on 5-HT turnover. To examine other possible interactions of these neuronal systems, we assessed the effect on 5-HT turnover of injecting substance P and 2-D-ala-met-enkephalin into the median raphe nucleus, and the effects of substance P on GABA turnover. Serotonin turnover was increased by 30% in the hippocampus after the injection of substance P (4 micrograms) into the median raphe, indicating an excitatory effect of substance P on the raphe-hippocampal system. Local injection of the metabolically stable metenkephalin analog 2-D-ala-met-enkephalin amide (10 micrograms) increased the hippocampal steady state content of 5-hydroxyindoleacetic acid (5-HIAA) by 60%. The data suggest an excitatory effect of met-enkephalin within the raphe nucleus. We attempted to estimate GABA turnover from the rate of disappearance of GABA after inhibition of glutamic acid decarboxylase by isoniazid and by the rate of accumulation of GABA after inhibition of GABA transaminase by gabaculine. Isoniazid, which is a competitive inhibitor, had too short and incomplete an action to be of use when injected intranuclearly. Gabaculine, which is an irreversible inhibitor, induced a rapid-onset increase in GABA content. This accumulation was linear up to 90 min. The injection fo gabaculine (80 ng) into the raphe increased GABA content by five times the control values, but hippocampal 5-HT and 5-HIAA contents were not significantly changed. Substance P injection increased the GABA turnover by 30%. Gabaculine seems a promising tool for detecting changes in GABA turnover.

Animals↗
PubMed1993

Syntheses and inhibitory effects on gastric lesions of trans-guanidinomethylcyclohexane carboxylic acid arylamides.

A novel series of trans-guanidinomethylcyclohexanecarboxylic acid (trans-GMCHA) arylamides was synthesized. The several trans-GMCHA arylamide derivatives showed more potent inhibitory effects on the stress- and HCl-ethanol-induced gastric ulcers than cetraxate in rats. In acute toxicity studies in mice, most amides showed such severe toxicity that all mice injected with these compounds (50 mg/kg, i.p.) died. However, mice injected with the trans-GMCHA (2'-,3'- and 4'-ethoxycarboxy)phenylamide (7, 8 and 9) which bear an alkyloxycarbonyl group at benzene ring survived. From these results, trans-GMCHA (2'-ethoxycarbonyl)phenylamide (7) was selected as a promising anti-ulcer agent.

Animals↗
PubMed1999

Gabapentin decreases the severity of dystonia at low doses in a genetic animal model of paroxysmal dystonic choreoathetosis.

The effects of the gamma-aminobutyric acid (GABA)-potentiating drug gabapentin (1-(aminomethyl) cyclohexaneacetic acid) on severity of dystonia were examined in a hamster model of idiopathic paroxysmal dystonic choreoathetosis. In the genetically dystonic hamster (dt(sz)) recent pharmacological and neurochemical studies suggested that disturbed GABAergic inhibition is involved in the pathogenesis. In line with a case report of beneficial effects in human paroxysmal dystonic choreoathetosis, gabapentin reduced the severity of dystonia in mutant hamsters at doses of 5 and 10 mg kg(-1) i.p. At higher doses (20 and 100 mg kg(-1)), gabapentin, however, failed to exert antidystonic effects. The GABApotentiating activity of gabapentin could explain the antidystonic effects of low doses, while the loss of efficacy at higher doses may be due to other mechanisms of gabapentin.

Acetates↗