Ferenc Andrasi

Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466.

The effects of GYKI 52466, a new 2,3-benzodiazepine with muscle relaxant and anticonvulsant properties, were investigated and compared to those of midazolam in electrophysiological experiments. The effects of the drugs on the reflex potentials evoked by afferent nerve stimulation and recorded from the spinal roots in unanesthetized spinal cats were studied. GYKI 52466 exerted a strong inhibitory effect on the monosynaptic as well as the polysynaptic ventral root reflexes, while the dorsal root responses decreased slightly. In contrast, midazolam markedly enhanced the dorsal root responses, did not modify the monosynaptic reflex and partially inhibited the polysynaptic reflex. The spontaneous firing of cerebellar Purkinje cells was depressed by midazolam, but not by GYKI 52466. These results suggest strongly that, contrary to the classical 1,4-benzodiazepines, potentiation of the GABA-A receptor-mediated inhibition does not play a significant role in the pharmacological actions of GYKI 52466.

New Non Competitive AMPA Antagonists

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.

The AMPA-antagonist talampanel is neuroprotective in rodent models of focal cerebral ischemia.

Cerebroprotection after administration of glutamate receptor antagonists has been well documented. The present study is intended to determine whether the non-competitive alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid (AMPA) receptor antagonist talampanel, known as antiepileptic drug, has neuroprotective effects in stroke models in rodents. The infarct size was measured in three models of stroke by 2,3,5-triphenyltetrazolium chloride staining. Therapeutic time window was also examined in rats subjected to 1h middle cerebral artery occlusion. The degree of neuroprotection was tested in mice, using 1.5, 2 h or permanent middle cerebral artery occlusions. Effect on photochemically induced thrombosis was investigated in rats applying 30 min time window after brain irradiation. Talampanel reduced the infarct size by 47.3% (p<0.01) after a 30 min delay and 48.5% (p<0.01) after 2 h delay following middle cerebral artery occlusion in rats. In mice, talampanel reduced the extension of the infarcted tissue at the levels of striatum and hippocampus by 44.5% (p<0.05) and 39.3% (p<0.01) after 1.5 h transient ischemia and still caused 37.0% (p<0.05) and 37.0% (p<0.05) inhibitions when 2 h occlusion was applied. In photothrombosis talampanel showed a 40.1% (p<0.05) inhibition. Protective actions of talampanel in various stroke models, in rats and mice, suggest a possible therapeutic role of the compound in stroke patients.

Preparation and antiarthritic activity of new 1,5-diaryl-3-alkylthio-1H-1,2,4-triazoles and corresponding sulfoxides and sulfones

Abstract A series of 1,5-diaryl-3-alkylthio-1H-1,2,4-triazoles and corresponding sulfoxides and sulfones was synthesized and evaluated as antiinflammatory agents in the rat adjuvant induced arthritis assay. Several analogues were found to be more potent than phenylbutazone and naproxen. Structure-activity relationships are discussed.

Structural analogues of some highly active non-competitive AMPA antagonists

Some 5-methyl analogues (14a-e) of the non-competitive AMPA antagonists 3-acylated 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3H-2,3-benzodi azepines (2,3) have been synthesized. Generally they show diminished or low biological activity but two derivatives (14a,b) reveal effects comparable to those of GYKI 52466 (1), the prototype non competitive AMPA antagonist.

Morphine and [D-Met2,Pro5]enkephalinamide do not show specific neuroleptic activity

Several conventionally used in vivo pharmacological assays were applied to examine whether morphine (M) and a potent enkephalin analogue, [D-Met2,Pro5]enkephalinamide (DMPEA) have haloperidol (H)-like neuroleptic activity. The apomorphine (A)-induced stereotypy and the conditioned reflex activity were inhibited by extremely low doses of H, while somewhat higher doses were needed to induce catalepsy or to suppress the A-elicited turning behaviour in rats with unilateral nigral lesion. M produced these effects only in doses higher than needed for analgesia. DMPEA, however, attenuated the A-elicited stereotypy already at a subanalgesic dose level but it was very weak in the other tests. Furthermore, neither M nor DMPEA inhibited the A-elicited stereotypy completely. Consequently, these drugs exhibit strikingly dissimilar relative potencies in the in vivo assays considered specific for neuroleptics. Our findings, in accordance with much of the data available, suggest that neither M nor DMPEA has a specific neuroleptic activity.