Synthesis and radioligand‐binding assay of 2,5‐disubstituted thiadiazoles and evaluation of their anticonvulsant activities

• Published in: Archiv der Pharmazie (Weinheim) 2020-12, Vol.353 (12), p.n/a
• Main Authors: Toolabi, Mahsa, Khoramjouy, Mona, Aghcheli, Ayoub, Ayati, Adileh, Moghimi, Setareh, Firoozpour, Loghman, Shahhosseini, Soraya, Shojaei, Rouhallah, Asadipour, Ali, Divsalar, Kouros, Faizi, Mehrdad, Foroumadi, Alireza
• Format: Article
• Language: English
• Subjects: 1,3,4‐thiadiazole; anticonvulsant agents; Anticonvulsants; benzodiazepine receptors; Binding sites; flumazenil; radioligand‐binding assay; Sleep
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000066

In this study, a number of 2,5‐disubstituted 1,3,4‐thiadiazoles were synthesized using an appropriate synthetic route, and their anticonvulsant activity was determined by the maximal electroshock seizure (MES) test and their neurotoxicity was evaluated by the rotarod test. Additionally, their hypnotic activity was tested using the pentobarbital‐induced sleep test. Compounds 7 (ED50 = 1.14 and 2.72 μmol/kg in the MES and sleep tests, respectively) and 11 (ED50 = 0.65 and 2.70 μmol/kg in the MES and sleep tests, respectively) were the most potent ones in the sleep test and anticonvulsant test, showing a comparable activity with diazepam as the reference drug. The results of in vivo studies, especially the antagonistic effects of flumazenil, and also the radioligand‐binding assay confirmed the involvement of benzodiazepine (BZD) receptors in the anticonvulsant and hypnotic activity of compounds 7 and 11. Finally, the docking study of compound 11 in the BZD‐binding site of the GABAA (gamma‐aminobutyric acid) receptor confirmed the possible binding of the compound to the BZD receptors. We concluded that the novel 1,3,4‐thiadiazole derivatives with appropriate substitution at positions 2 and 5 of the heterocyclic ring had a good affinity to BZD receptors and showed significant efficacy in the pharmacological tests. In this study, 2,5‐disubstituted 1,3,4‐thiadiazoles were synthesized as anticonvulsant agents. Compound 11 showed a good anticonvulsant activity in the maximal electroshock seizure test. The anticonvulsant effect of compound 11 was completely blocked by flumazenil and the involvement of benzodiazepine receptors was confirmed by the radioligand‐binding assay.