Antiglycation, radical scavenging, and semicarbazide-sensitive amine oxidase inhibitory activities of acetohydroxamic acid in vitro.

Advanced glycation endproducts (AGEs) can promote intracellular reactive oxygen species production, and the levels of AGEs are highly correlated with cardiovascular disease and diabetes complications. Acetohydroxamic acid (acetH) is a bacterial urease inhibitor drug used to treat kidney stones and infections in the urinary tract, and hydroxyurea (HU) is a drug used for antineoplasm and sickle cell diseases. Both acetH and HU are hydroxamic acid derivatives. It was found that acetH and HU at 2.5 or 5 mM showed anti-AGE formation by lowering the AGEs' fluorescent intensities and Nε-(carboxymethyl)lysine formation in bovine serum albumin/galactose models, and both showed better and significant differences (P<0.05) compared to the positive control of aminoguanidine. Regarding radical scavenging activities, the half-inhibition concentrations (IC50) of acetH against α,α-diphenyl-ß-picrylhydrazyl radical and hydroxyl radical were 34.86 and 104.42 µM, respectively. The IC50 of acetH against semicarbazide-sensitive amine oxidase was 10.56 µM, and acetH showed noncompetitive inhibition respective to the substrates (benzylamine). The antiglycation, antioxidant, and semicarbazide-sensitive amine oxidase inhibitory activities of acetH prove that it has the potential for treating cardiovascular disease and diabetes complications and it needs further investigation in animal models.

Amine oxidases as important agents of pathological processes of rhabdomyolysis in rats.

In this study we have tested an idea on the important role of amine oxidases (semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase) as an additional source of oxidative/carbonyl stress under glycerol-induced rhabdomyolysis, since the enhanced formation of reactive oxygen species and reactive carbonyl species in a variety of tissues is linked to various diseases. In our experiments we used the sensitive fluorescent method devised for estimation of amine oxidases activity in the rat kidney and thymus as targeted organs under rhabdomyolysis. We have found in vivo the multiple rises in activity of semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase (2-4.5 times) in the corresponding cell fractions, whole cells or their lysates at the 3-6th day after glycerol injection. Aberrant antioxidant activities depended on rhabdomyolysis stage and had organ specificity. Additional treatment of animals with metal chelator 'Unithiol' adjusted only the activity of antioxidant enzymes but not amine oxidases in both organs. Furthermore the in vitro experiment showed that Fenton reaction (hydrogen peroxide in the presence of iron) products alone had no effect on semicarbazide-sensitive amine oxidase activity in rat liver cell fraction whereas supplementation with methylglyoxal resulted in its significant 2.5-fold enhancement. Combined action of the both agents had additive effect on semicarbazide-sensitive amine oxidase activity. We can assume that biogenic amine and polyamine catabolism by amine oxidases is upregulated by oxidative and carbonyl stress factors directly under rhabdomyolysis progression, and the increase in catabolic products concentration contributes to tissue damage in glycerol-induced acute renal failure and apoptosis stimulation in thymus.

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.

GABA-ergic mechanisms in the anticonvulsive activity of newly-synthesized barbiturates. I. Effects of barbiturates on the convulsive action of GABA-antagonists.

The anticonvulsive activity of seven newly-synthesized derivatives of barbituric acid, having a hydroxylamins groups substituted in second position, with respect to convulsive agents related with the GABA-ergic transmitter system: picrotoxin, bicuculline, thiosemicarbazide and 3-mercaptopropionic acid, was studied in experiments on mice. The anticonvulsive activity of these compounds in allylglycine-induced convulsions was investigated in experiments on rats, and was compared to that of well-known drugs, such as pentobarbital, phenobarbital, allobarbital and diphenylhydantoin. The results obtained show that the hydroxylamine derivatives of barbituric acid HB-2 (2-hydroxylamino-5-ethyl-5-propylbarbituric acid) and HB-7 (2-hydroxylamino-5-ethyl-5 sec. pentylbarbituric acid) have the most pronounced anticonvulsive activity, which suggests the considerable importance of the participation of GABA-ergic transmission in the realization of this activity.

[Effect of antidepressants on the convulsive action of thiosemicarbazide, strychnine and corasol]. / Vliianie antidepressantov na sudorozhnoe deistvie tiosemikarbazida, strikhnina i korazola.

Orally administered amitryptiline (25 and 50 mg/kg) protected animals against fatal convulsions induced by thiosemicarbazide, strychnine and metrazole. Vilaxazine had a protecting effect against death induced by strychnine. Impramine, maprotiline, mianserine and pirlindole (pyrazidol) only somewhat prolonged the latend period of convulsions and death, while incazane, caroxazone, nomifenzine and trazodone had practically no effect on the action of the three convulsants under study.

[GABA-ergic component in the action of the tranquilizing agent mebikar]. / GAMK-érgicheskii komponent v deistvii trankvilizatora mebikara.

The paper is concerned with studies into the effect of the tranquilizer mebicar, a derivative of tetra-N-alkyl bicyclic bisureas, on the GABA-ergic system. The drug in doses of 250-1500 mg/kg (1/15-1/2 LD50) increased the preconvulsive period upon thiosemicarbazide administration, inconsistently changed the effects of picrotoxin and displayed antagonism in regard to bicucullin. Upon 2-week administration the drug reduced the GABA content in the rat brain. A hypothesis is advanced of mebicar-associated facilitation of the inhibitory GABA-ergic transmission.

[Anticonvulsant action of di-N-propylacetate combined with benzodiazepines, phenobarbital and phenytoin]. / Protivosudorozhnoe deistvie di-N-propilatsetata v sochetanii s benzodiazepinami, fenobarbitalom i fenitoinom.

The combined use of di-n-propylacetate with phenazepam, diazepam, phenobarbital or phenytoin was shown to be followed by reciprocal potentiation of the anticonvulsant activity of the drugs in a variety of experimental epileptic seizures in mice according to the tests of shock and antagonism with corasole and thiosemicarbazide. The potentiating effect of the subthreshold dose of di-n-propylacetate on anticonvulsant effects of benzodiazepines, phenobarbital and phenytoin was more pronounced than the effect of the drugs administered in the subthreshold doses on the anticonvulsant activity of di-n-propylacetate. Of both combinations, di-n-propylacetate plus benzodiazepines proved to be most efficacious one. The unidirectional effect of the combined drugs on the different stages of the development of GABA-ergic system inhibitory function in the CNS activity is assumed to be of importance in the mechanism of reciprocal potentiation.

[Participation of GABA-ergic structures in producing the effects of haloperidol]. / Ob uchastii GAMK-ergicheskikh struktur v realizatsii éffektov galoperidola.

A study was made of the effect of haloperidol on convulsions induced in mice by bicuculline and thiosemicarbazide and on the recovery cycles of the primary response in the rat sensorimotor cortex. In doses of 0.3--0.5 mg/kg producing a tranquilizing effect, haloperidol exerts a protective action in convulsions induced by bicuculline blocking of the GABA receptors and enhances the depression of the testing response during recovery cycle of the rat sensorimotor cortex primary response. It means that over this dosage range haloperidol potentiates GABA-induced effects. An increase in the neuroleptic dose up to 1--2 mg/kg entails disappearance of the efficacy shown by both the tests. The authors' own and reported data suggest an important role played by the postsynaptic GABA-positive effect in realization of the tranquilizing action of haloperidol and other neurotropic agents.

Novel anxiolytic agents derived from alpha-amino-alpha-phenyl-o-tolyl-4H-triazoles and -imidazoles.

Several new alpha-amino-alpha-phenyl-o-tolytriazoles and -imidazoles have been prepared in one step by means of a novel reductive rearrangement of the corresponding benzodiazepines with hydrazine hydrate. These new triazoles were found to have moderate sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes at higher doses than did diazepam) but were very potent antagonists of the clonic convulsions induced in mice by the administration of pentylenetetrazole. Furthermore, they antagonized the lethality induced by thiosemicarbazide. While these new compounds were very active in mice, most were inactive in rats. These results are discussed with reference to the metabolism of compound 13.

Synthesis and pharmacology of novel anxiolytic agents derived from 2-[(dialkylamino)methyl-4H-triazol-4-yl] benzophenones and related heterocyclic benzophenones.

A series of novel [(dialkylamino)methyl-4H-1,2,4-triazol-4-yl]benzophenones and related compounds has been prepared via total synthesis from substituted aminodiphenylmethanes or by hydrolysis and subsequent methylation of triazolobenzodiazepines. These new triazole compounds were found to have potent sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes). In addition, the title compounds antagonized the clonic convulsions induced in mice by the administration of pentylenetratrazole (Metrazol, 85 mg/kg), with ED50's varying from 2.0 to 23.0 mg/kg, and the lethality induced by thiosemicarbazide, with ED50's varying from 0.02 to 9.0 mg/kg. In several biological tests, the potency of seven new benzophenone derivatives approached or exceed that of diazepam (35a) or its glycylaminobenzophenone analogue 36.