[NEUROCHEMICAL STUDY OF TROPOXIN EFFECTS ON THE CONTENT OF MONOAMINES AND ITS METABOLITES IN WISTAR RAT BRAIN STRUCTURES].

The influence of perspective anti-migraine drug tropoxin on the content of monoamines and related metabolites in Wistar rat brain structures, including frontal cortex (FC), hypothalamus, nucleus accumbens (NA), striatum, and hippocampus, has been studied using HPLC/ED technique. Tropoxin (10 mg/kg) induced a 30% decrease (p < 0.05) in dopamine (DA) level in FC as well as norepinephrine content in NA, while the concentrations of DA metabolites DOPAC and HVA in the hypothalamus were found to increase. The injection of tropoxin in a dose of 20 mg/kg led to an increase in HVA level in hypothalamus as well as seroto- nin metabolite 5-HIAA content in NA. The obtained data provide evidence that tropoxin predominantly influenced the activity of dopaminergic system while the drug effects on the parameters of serotoninergic link seem to be rather mild.

[STUDYING ANXIOLYTIC AND ANTIDEPRESSANT PROPERTIES OF 2,2,6,6-TETRAMETHYLPIPERIDONE DERIVATIVE.]

Neuropharmacological properties of LK-998 (3,4,5-trimethoxy-N'-(2,2,6,6-tetramethylpiperidin-4-yliden)benzohydrazide), a 2,2,6,6-tetramethylpiperidone de- rivative have been studied. LK-998 exhibited anxiolytic activity in doses of 10 and 20 mg/kg, significantly increasing the duration of animal staying of in open arms of the elevated plus maze as well as the number of arm entries. The efficiency of drug tested in a dose of 10 mg/kg was comparable with that of afobazole in a dose of 5 mg/kg. In marble burying test, it was also found that animals treated with LK-998 at 10 mg/kg buried a close number of balls to that as rodents treated with afobazole at 5 mg/kg. At the same time, LK-998 in doses 10 and 20 mg/kg did not produce any antidepressant action in the learned helplessness test. Thus, LK-998 in a dose of 10 mg/kg has anxiolytic and anticompulsive effects comparable to those of afobazole at a dose of 5 mg/kg. The study of potenti- al side effects of LK- 998 in a dose of 200 mg/kg (i.e., 20 times the therapeutic dose of 10 mg/kg) showed that the drug tested caused neither side effects nor symptoms of neurological deficiency within 24 hours and on longer terms (4, 10 and 14 days after administration).

[Cerebrovascular serotonin antagonists and agonist among tropan derivatives].

A series of new tropan derivatives have been synthesized and investigated, which can both weaken and potentiate the serotonin-induced cerebrovascular constrictory reactions. The compound LK-728 produces a pronounced antiserotonin cerebrovascular action comparable to that of tropoxin, but being superior to the reference drug in the effect duration. On the contrary, another tropan derivative LK-769 enhances the cerebrovascular response to serotonin. A similar effect was demonstrated with the well-known antimigraine agent sumatriptan, which is an agonist of 5HT1B/1D receptors. The ability of sumatriptan to increase the local cerebral blood flow which was observed in our experiments, may also play an important role in the mechanism of the antimigraine action produced by this serotonin receptor agonist.

[Interaction of tropoxin and its molecular fragments tropan and 3,4,5-trimethoxybenzoate with serotonin receptors of cortical neurons in the rat brain (a microionophoretic study)].

The effects of the antimigraine drug tropoxin and its main molecular fragments - tropan and 3,4,5-trimetoxybenzoate (TMB) - on the serotonin sensitivity of postsynaptic neuronal membrane in rat brain sensorimotor area has been studied using a microionophoretic (MIP) technique. All the three substances significantly reduce the excitatory neuronal response to serotonin, which is manifested by an increase in the rate of the spontaneous action potentials. With respect to the antiserotonin effect, the substances can be arranged in the following order: tropoxin > tropan > TMB. The sum of the effects of tropan and TMB (for both simultaneous and separate action upon the target cells) was significantly lower than the effect of tropoxin in all doses (MIP currents). It is concluded that a pronounced antiserotonin effect of tropoxin is produced only provided that the entire molecular configuration is retained. Tropan and TMB, being tropoxin metabolites, are probably capable of prolonging the antimigraine action upon the decay of tropoxin in the organism. A relationship between the structure and action of serotonin receptor blockers of the tropan series is discussed.

[Tropoxin and cerebrovascular effects of serotonin]. / Tropoxin i tserebrovaskuliarnye éffekty serotonina.

The effect of serotonin on the brain blood supply was studied in rats before and after ischemic damage. The ischemic damage, induced by ligation of the middle meningeal artery, markedly enhanced the constrictor effect of serotonin on the brain vessels. Tropoxin, a 5HT2 receptor blocker, completely eliminated these cerebrovascular effects of serotonin.

[Tropoxin--a new serotonin antagonist and potential antimigraine agent]. / Tropoksin--novyi antagonist serotonina i potentsial'noe protivomigrenevoie sredstvo.

The search for serotonin antagonists with cerebrovascular activity was conducted among newly synthesized aromatic and heteroaromatic ethers of tropinone oxim. One of these compounds, namely, hydrochloride-3(3,4,5-trimethoxybenzoiloxiimino-1)-8-methyl-8-a zab icyclo [3,2,1] octane, called tropoxin, prevented the development of serotonin-induced constriction of cerebral vessels in vitro and in vivo experiments. This effect was demonstrated also in experiments with oral administration of the drug. Tropoxin was found to possess affinity for 5-HT2 receptors of the rat brain. Tropoxin surpasses the anti-migraine drug methysergide in antiserotonin cerebrovascular activity. This allows tropoxin to be recommended for study as a means for the treatment of migraine.

[Central cholinolytic effect of tropane derivatives: structure-activity relationship]. / Tsentral'nyi kholinoliticheskii éffekt proizvodnykh tropana: sviaz' struktury i deistviia.

The effect of two tropane derivatives on the electric neuronal activity in sensorimotor cortex was studied in rabbits using microiontophoretic method. Unlike atropine they lack aryl and hydroxyl, but possess morpholine and piperazine. The effects of both drugs were opposite to those of acetylcholine. Simultaneous application of tropane derivatives and acetylcholine to one neuron decreased both excitatory and inhibitory neuronal responses to acetylcholine. It is concluded that aryl and hydroxyl are not necessary for tropane derivatives to reveal their central cholinolytic activity.

[Mechanism of the central effects of tropane]. / K mekhanismu tsentral'nykh éffektov tropana.

The effect of tropan on exocellular-recorded electrical activity of brain sensorimotor cortical and ventrolateral thalamic neurons was studied in acute experiments on rabbits. Tropan was injected intravenously in a dose of 1-5 mg/kg and applied microiontophoretically to individual neurons. With both routes of administration tropan increased the frequency of spontaneous activity of the majority of cortical and thalamic neurons in the dose-dependent form. The inhibitory action of the microiontophoretically applied catecholamines noradrenaline and dopamine on the activity of brain cortical neurons does not change under the effect of tropan. The stimulatory effect of catecholamines on ventrolateral thalamic neurons is potentiated by tropan. It is suggested that excitation of cortical and subcortical neurons, as well as potentiation of stimulatory catecholaminergic effects in the subcortex underlie the central stimulant effect of tropan.

[Effect of cocaine molecule fragments on the central nervous system]. / Deistvie fragmentov molekuly kokaina na tsentral'nuiu nervnuiu sistemu.

The influence of ecgonine, tropine, tropinon, and some of their derivatives, propan, N-methylpyrrholidine, N-methylpiperidine on impulse summation in the central nervous system, conditioned reflex of avoidance, antagonism to hexenal, synergisim to cocaine and also their toxicity (LD50) have been studied under experimental conditions. As shown, benzoyl-ecgonine, ecgonine methyl ester, ecgonine, tropine, pseudotropine, carbomethoxytropinon, tropinon, tropine, tropan N-methylpyrrolidine, and N-methylpiperidine produced a pronounced stimulating effect on the central nervous system activity; in this respect they were similar to cocaine. The following conclusions were made: the substances whose molecules contained tropan structure or one of its fragments possess the central stimulating effect. The stimulating effect of cocaine on the central nervous system could be due to the tropan fragment of its molecule.