[COMPARISON OF CHRONIC ANTICONVULSANT ACTIVITY AND SAFETY OF IEM-2062, SODIUM VALPROATE AND ME-MANTINE IN THE PENTYLENETETRAZOL KINDLING MODEL IN RATS].

IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], causing a combined block NMDA and AMPA receptors, after chronic oral administration in doses, respectively, 0.3 and 3 mg/kg, induce maximal anticonvulsant effect in the pentylenetetrazol kindling rats because decrease the number of completely kindling rats by 100 %, and also decrease in 2.5-3.3 times the average severity of clonic-tonic kindling seizures. IEM-2062 causes significant anticon- 299 vulsant effects in the widest range of doses, 1-48 mg/kg, which is 24-22 times more than that of memantine (12-20 mg/kg) and sodium valproate (100-200 mg/kg). Sodium valproate and memantine cause significant disturbances of locomotor activity in the «open field¼ test in doses causing maximal anticonvulsant effect in the kindling rats. At the same time IEM-2062 cause disturbance of locomotor activity only in very high dose of 92 mg/kg, which exceeds in 30.7 times the dose causing the maximum anticonvulsive effect in the kindling rats. Thus, IEM-2062 reduces the severity of kindling seizures in 1.7-1.9 times stronger than sodium valproate and memantine and also by 30.7 times is safer than sodium valproate and memantine.

Comparison of Pharmacological Potency and Safety of Glutamate Blocker IEM-1913 and Memantine.

Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino)-butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors.

[Stimulation of gastric mucosa afferents by phenylephrine potentiates anticonvulsive and eliminates sedative action of sodium valproate in the pentylenetetrazol kindling model in rats].

Sodium valproate after chronic intragastric administration in the high dose of 100-200 mg/kg eliminates generalized clonic-tonic pentylenetetrazol seizures in 100 % of rats, but only in 33-57 % of rats it prevents local clonic kindling seizures. Strong sedation is induced by the specified doses of sodium valproate. The combined oral chronic administration of phenylephrine in threshold, noneffective alone dose of 0.2 mg/kg and sodium valproate in high doses of 100 mg/kg and 200 mg/kg potentiates anticonvulsive action of sodium valproate, because prevents both clonic-tonic kindling. seizures in 100 % of rats and clonic kindling seizures in 86-100 % of rats, and also it increases in 1.7-1.9 times anticonvulsive activity of valproate. The specified combinations of sodium valproate with phenylephrine do not produce the sedative side effect. The basis of the mechanism of potentiation of anticonvulsive action and elimination of sedative action of sodium valproate in high doses is the stimulation of gastric mucosa afferents by phenylephrine.

Phenylephrine potentiates the anticonvulsant effect and neutralizes the sedative effect of diazepam in rats upon combined intragastric administration.

High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole-induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine.

[The search for selective blockers of NMDA and AMPA/kainate receptors in a series of bis-ammonium compounds with adamantyl radicals]. / Poisk izbiratel'nykh blokatorov NMDA i AMPA/kainatnykh retseptorov v riadu bis-ammonievykh soedinenii s adamantil'nymi radikalami.

Two groups of substances capable of selectively blocking the NMDA and AMPA/kainate receptors in experiments on intact animals were found in a series of bis-ammonium compounds with adamantyl radicals. The selective NMDA receptor blockers (IEM-1754, IEM-1755, IEM-1752), as well as the reference agents MK-801 and memantine, produced anticonvulsant, anti-ischemic, and antihypoxant effects and prevented the loss of experimental animals from toxic doses of NMDA. The selective AMPA/kainate receptor blockers (IEM-1553, IEM-1751, IEM-1592, and DNQX)) also produced the anticonvulsant, anti-ischemic, and antihypoxant effects, but did not prevent from the loss of animals caused by the toxic doses of NMDA. The maximum activity was observed for IEM-1754, the activity of which exceeded that of MK-801 (by a factor of 5-10) and memantine (by a factor of 300-800) in all the test objects.

[The participation of glutaminergic transmission in the mechanism of movement disorders induced by reverse rotation in white mice]. / Uchastie glutamatergicheskoi peredachi v mekhanizme dvigatel'nykh narushenii, vyzvannykh reversivnym vrashcheniem belykh myshei.

Administration of MK-801 or IEM-1754 prevented akinesia in mice induced by reversing rotation, not less effectively than scopolamine. Quaternary adamantane derivative IEM-1857 was ineffective. IEM-1925 enhanced the locomotor disturbance induced by reversing rotation due, probably, to different spectrum of its antiglutamate action. The data obtained suggest involvement of glutamate synaptic transmission in development of locomotor disturbances of a vestibular origin.

[The blockade of glutaminergic and cholinergic ion channels by adamantane derivatives]. / Blokada glutamat- i kholinergicheskikh ionnykh kanalov proizvodnymi adamantana.

It has been shown that a homologous series of adamantane derivatives of general structure Ad-CH2-N+H2-(CH2)5-N+R3, where Ad, adamantane, R varied from H (hydrogen) to t-Bu (tertiary butyl), blocks the open state of postsynaptic activated channels. In the presence of the drugs studied the decay of evoked cholinergic postsynaptic currents in frog neuromuscular junction could be fitted by two exponentials. However, the rate constants of interaction of blocker with channel did not depend on the R structure and membrane potential. The rate of blockade of glutamatergic postsynaptic currents in insect neuromuscular junction increased as the radicals at nitrogen atom became heavier, but was independent on membrane potential. The drugs studied affected in voltage dependent manner the kinetic properties of single channels (recorded in outside-out patches excised from cultured neurones of embryonic rat brain cortex) induced by NMDA application. Each of these compounds evoked fast flickering of single channels between an open and blocked state. Drugs effectively prevented the convulsions evoked by intraventricular injection of NMDA into mouse brain. The compound IEM-1754 that was the most potent blocker in the experiments on NMDA-activated single channels possessed six times higher anticonvulsant activity than dizocilpine (MK-801).