Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3H-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms

Abstract

About 70 million people suffer from epilepsy—a chronic neurodegenerative disease. In most cases, the cause of the disease is unknown, but epilepsy can also develop as the result of a stroke, trauma to the brain, or the use of psychotropic substances. The treatment of epilepsy is mainly based on the administration of anticonvulsants, which the patient must most often use throughout their life. Despite significant progress in research on antiepileptic drugs, about 30% of patients still have drug-resistant epilepsy, which is insensitive to pharmacotherapy used so far. In our recent studies, we have shown that 4-alkyl-5-aryl-1,2,4-triazole-3-thiones act on the voltage-gated sodium channels and exhibit anticonvulsant activity in an MES (maximal electroshock-induced seizure) and 6Hz test in mice. Previous studies have shown their beneficial toxic and pharmacological profile, but their effect on a living organism during chronic use is still unknown. In the presented study, on the basis of the previously conducted tests and the PAMPA (parallel artificial membrane permeability assay) BBB (blood–brain barrier) test, we selected one 1,2,4-triazole-3-thione derivative—TP-315—for further studies aimed at assessing the impact of its chronic use on a living organism. After long-term administration of TP-315 to Albino Swiss mice, its effect on the functional parameters of internal organs was assessed by performing biochemical, morphological, and histopathological examinations. It was also determined whether the tested compound inhibits selected isoforms of the CYP450 enzyme system. On the basis of the conducted tests, it was found that TP-315 does not show nephrotoxic nor hepatotoxic effects and does not cause changes in hematological parameters. In vitro tests showed that TP-315 did not inhibit CYP2B6, CYP2D6, CYP3A4, or CYP3A5 enzymes at the concentration found in the serum of mice subjected to long-term exposure to this compound.

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

“…Thus, based on docking studies it might be concluded that designed s -triazoles 3 and 4 are able to inhibit Nav1.7 through a voltage-sensor trapping mechanism, similar to that depicted for the native antagonist GX-936. What is important, according to HYDE scoring function ( Figure 3 ) the elongation of the N4 alkyl chain from the butyl to the hexyl ( 1 , 2 ) led to an enhanced receptor-ligand interactions, which is consistent with the experimental results [ 17 ], whereas the HYDE scores are not much different between s -triazoles with the methylene and the ethylene linker ( 1 vs. 3 and 2 vs. 4 , respectively). Furthermore, our docking studies confirm that the binding mode of s -triazoles 1 and 2 is generally very similar to that of s -triazoles 3 and 4 , with some exceptions.…”

“…According to the literature, compounds possessing 1,2,4-triazole ring in their structures are characterized by high antiepileptic potential [ 10 , 11 , 12 , 13 , 14 ]. Among them, 4-alkyl-5-aryl-1,2,4-triazole-3-thione derivatives express anticonvulsant activity both against tonic–clonic seizures and in an animal model of drug-resistant epilepsy [ 15 , 16 , 17 ]. Mechanistic studies revealed that these compounds could not affect the GABAergic neurotransmission, neither directly nor allosterically; however, they acted as voltage-gated sodium channel ligands in a low micromolar range [ 18 ].…”

Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies

“…Moreover, in living organisms, there was neither alteration of hepatic and renal function nor change of hematologic parameters after long-term administration of TP-315. At a concentration similar to the concentration measured in the tested mice, the activities of the enzymes CYP2B6, CYP2D6, CYP3A4, and CYP3A5 were not significantly inhibited by TP-315, although CYP2C19 was [84]. Potential interaction with some marketed ASMs that are substrates of CYP2C19, such as diazepam, phenytoin, and valproic acid, deserves more investigations.…”