Anticonvulsant activity of 4-urea-5,7-dichlorokynurenic acid derivatives that are antagonists at the NMDA-associated glycine binding site

Abstract

Twelve 4-urea-5,7-dichlorokynurenic acid derivatives were synthesized by reacting the 4-tosylimino derivative of 5,7-dichlorokynurenate methyl ester first with triphosgene and then with a secondary amine. Compounds were screened in mice for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole (Met), and threshold tonic extension (TTE) tests. A rotorod test was used to determine neurotoxicity. Seven of the derivatives had anticonvulsant activity in TTE testing at 100 mg/kg. One compound, 2-methyl carboxylate-5,7-dichloro-4-([¿diphenylamino¿-carbonyl]amino)-quino line, had an ED50 value of 134 mg/kg (95% conf. int.: low-78.5, high-205.7; slope 1.9, SE = 0.44) in TTE testing. Two derivatives had MES activity. Only one compound, an N,N-diethylamino derivative, was neurotoxic in the rotorod test. Compounds were screened at a 10-microM concentration for activity in displacing 5,7-dichlorokynurenic acid from synaptosomal membrane fragments. Since 9 of the 12 compounds synthesized and tested have demonstrated anticonvulsant activity, this class of chemicals offers promise for the production of useful therapeutic agents.

In Situ–Produced 7‐Chlorokynurenate Has Different Effects on Evoked Responses in Rats with Limbic Epilepsy in Comparison to Naive Controls

“…Several such site‐selective compounds have been generated and show potent anticonvulsant effects in experimental animals, but none of these compounds has so far been assessed for antiepileptic efficacy in humans (34). This group of agents includes 7‐Cl‐KYNA, the first selective glycine B ‐receptor antagonist synthesized with an IC 50 of 560 n M (35), which cannot be developed for clinical use because of its inability to enter the brain effectively after peripheral administration (9,10). We therefore used a prodrug approach, taking advantage of the fact that 4‐Cl‐KYN readily penetrates the blood–brain barrier and is rapidly converted to 7‐Cl‐KYNA in the brain (12,36).…”

“…Unfortunately, early attempts at attenuating the function of these receptors by using conventional NMDA‐receptor antagonists revealed serious adverse side effects (4,5). For reasons that are not fully understood, these harmful consequences of direct NMDA‐receptor blockade can be avoided by targeting the glycine co‐agonist (glycine B ) site on the receptor for seizure suppression (6–9).…”

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…Thiokynurenates are also potent non-competitive antagonists of the NMDARs. Substitution of a thio group for the hydroxyl group in position 4 of KYNA increased the potency and chlorination of position 7 or 5 and 7 of 4-thio-KYNA and further increased potency in ileal myenteric plexus and for [ 3 H]Gly binding [133]. 4-urea-5,7-di-Cl-KYNA derivatives exerted anticonvulsant activity in maximal electroshock, subcutaneous pentylenetetrazole, and threshold tonic extension tests in mice [133].…”

Recent developments in glycine antagonists

“…Researchers from the University of North Alabama [32,123], in 1998 patented a number of 4-urea-5,7-dichlorokynurenic acid derivatives which were obtained after screening at a 10 µM concentration for their ability to displace 5,7-dichlorokynurenic acid from synaptosomal membrane fragments. The positive compounds were screened in mice for anticonvulsant activity using maximal electroshock (MES), sc.…”