New phenyl-glycinamide derivatives with hybrid structure as new effective anticonvulsant candidates

Epilepsy is recognized as one of the most common neurological disorders. Notably, despite huge advances in epilepsy studies and approval of several new antiseizure drugs, in nearly 30% of patients pharmacotherapy does not produce expected improvement and they suffer from drug resistant epilepsy (DRE). In recent years development of new drugs for the treatment of multifactor diseases such as Alzheimer's disease, epilepsy and pain of various origin but also diseases with high risk of drug resistance is focused on multifunctional compounds which possess predominantly hybrid structures. Hybrid molecules are compounds that contain several pharmacophores merged on one chemical scaffold, which gives the possibility of interaction with more than one molecular target through the use of one substance. Bearing in mind the assumptions of multi-target strategy in the current studies, a series of 22 new chemically original compounds has been obtained. These compounds merge chemical fragments of well-known TRPV1 antagonists (e.g. BCTC) and potent anticonvulsant KA-104 described in our earlier studies. The compounds obtained possess wide spectrum of activity in the preclinical studies, namely in the maximal electroshock (MES) test, the psychomotor 6 Hz (32 mA) seizure model, and in the 6 Hz (44 mA) model of DRE. Additionally, these substances were effective in ivPTZ seizure threshold test in mice. Their mechanism of action is probably multimodal and involves TRPV1 receptor antagonism, as well as inhibition of fast sodium and calcium currents. Furthermore, in vitro studies proved beneficial ADME-Tox properties. The studies were supported by National Science Centre, Poland grant UMO-2017/27/B/NZ7/00249.