[Extracellular level of neuroactive amino acids in the rat neostriatum after treatment with psychostimulants (microdialysis study)]. / Vnekletochnoe soderzhanie neiroaktivnykh aminokislot v neostriatume krys pri deistvii psikhostimuliatorov (mikrodializnoe issledovanie).

The effects of acute and subchronic (four times with a 2-h interval) intraperitoneal administration of d-amphetamine and sydnocarb in equimolar doses (5 and 23.8 mg/kg, respectively) on the intracellular level of glutamate, asparate, taurine, and alanine in neostriatum of male Sprague-Dawley rats anesthetized with halothane was studied. It was shown that repeated introduction of the psychostimulants leads to a significant increase in the content of all four neuroactive amino acids in neostriatum dyalisates. However, the effects of sydnocarb were less pronounced as compared to those of d-amphetamine, which is indicative of a lower neurotoxic potential of the former drug and confirms a significant difference in the neurochemical mechanisms of action of the two drugs studied. The massive increase in the extracellular content of taurine probably reflects hyperactivation of the glutamatergic transmission in the neostriatum and may serve as a marker of neurotoxicity.

Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine.

Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-fos protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH.

Effects of acute toxic doses of psychostimulants on extracellular levels of excitatory amino acids and taurine in rats: comparison of d-amphetamine and sydnocarb.

We used microdialysis to study how acute toxic doses of d-amphetamine and sydnocarb [3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine], an original Russian psychostimulant, affect extracellular levels of glutamate, aspartate, and taurine in the neostriatum of halothane-anesthetized male Sprague-Dawley rats. The administration of d-amphetamine (5.0 mg/kg x 4 i.p.) caused gradual fivefold increases in the extracellular glutamate and taurine levels and moderate increases in the extracellular aspartate level. Sydnocarb administration (23.8 mg/kg x 4 i.p., a dose equimolar to 5.0 mg/kg d-amphetamine) elicited a marked increase in the extracellular aspartate level and a small increase in the extracellular level of glutamate. The extracellular taurine level increased only after the last (fourth) injection. We conclude that a massive increase in extracellular taurine reflects hyperactivation of glutamatergic neurotransmission elicited by acute toxic dose of d-amphetamine. Sydnocarb seems to be less neurotoxic than d-amphetamine, because it elicits lesser changes in the extracellular levels of glutamate and taurine.

Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.

Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity.

Synthesis and antiinflammatory, analgesic, and antipyretic testing of 4-[1-oxo-(3-substituted aryl)-2-propenyl]-3-phenylsydnones and of 3-[4-[3-(substituted aryl)-1-oxo-2-propenyl]phenyl]sydnones.

Two series of styrylcarbonyl 3-phenylsydnone derivatives, 4-[1-oxo-(3-substituted aryl)-2-propenyl]-3-phenylsydnones (series 1, 1-21) and 3-[4-[3-(substituted aryl)-1-oxo-2-propenyl]phenyl]sydnones (series II, 22-40), were synthesized and evaluated pharmacologically at a dose of 100 mg/kg po. Eleven compounds in series I plus one in series II and six in series I plus seven in series II were active in the carrageenan-induced edema and acetic acid-induced writhing assays, respectively. Compound 35 in the latter assay showed activity somewhat similar to that of the positive control drug, aspirin, administered at the same dosage. Compounds 11, 17, and 23 showed activity in both assays, and 23 also was active in the adjuvant-induced arthritis assay.

[Combined action of caffeine and sydnocarb]. / Kombinirovannoe deistvie kofeina i sidnokarba.

Combined application of two stimulants caffeine and sydnocarb (a sydnonimine derivative) was studied in rabbits, rats and mice using the method of summation of impulses in the central nervous system, the method of conditioned avoidance response, forced swimming and hexobarbital sleep in order to find out the changes in their main and side effects. It was established that the main stimulant effect of the drug combination given in optimal doses appeared to be additive, while side effects on the ECG and blood pressure remained unchanged.

[Pharmacological activity of the optical isomers of sydnocarb]. / Farmakologicheskaia aktivnost' opticheskikh izomerov sidnokarba.

Of the two optical isomers of sydnocarb, only 1- (or 1R)-isomer exerts a stimulant effect on the central nervous system. By its stimulant action it differs from both optical isomers of amphetamine. The activity of 1-(IR)-sydnocarb as measured by the locomotor excitation test is similar to that of d(1S)-amphetamine but is significantly less powerful as indicated by stereotypy, hyperthermia, anorexigenic action and antagonism to the depressant effects of reserpine.

[Pharmacological properties of sidnocarb analogs]. / Farmakologicheskie svoistva nekotorykh analogov sidnokarba.

It was shown in experiments on mice and rats that increased hydrophobic properties of the phenylcarbomoyl radical to sydnocarb attained by introduction of halogens of trifluoromethylene in the benzene ring is conducive to the production of compounds that are similar to sydnocarb by the spectrum of the central stimulant action but are 2--4 times more active. In contradistinction to phenamine and its analogues the replacement of beta-phenylisopropyl chain by beta-phenylethyl one is not followed by an abrupt decrease in the activity in the series of compounds tested.