Dichloro-substituted phenyl amino propanamides exhibit anticonvulsant effect and reduce inward sodium ion current (Na_V1.6)

Abstract

This research studied the anticonvulsant properties of three synthesized isomers of dichloro-substituted phenyl amino propanamides in rodents and determined their effects on votage-gated sodium channels (Na_V1.6) stably expressed in Human Embryonic Kidney (HEK Cells 293). 2,3-, 2,5- and 3,4- Dichloro anilines were reacted with acrylamide according to Michael-type addition reaction to obtain their corresponding isomers; DCP23, DCP25 and DCP34. Each isomer was evaluated for anticonvulsant effects using maximal electroshock (MES)- and pentylenetetrazole (PTZ)- induced seizure models in mice; tested against PTZ-induced kindling in rats and its synergistic effect with fluphenamic acid in mice. Effects of DCP23 and DCP25 were studied on voltage-gated sodium channels (Na_V1.6) at different states of the channel, using electrophysiology techniques. The test compounds generally offered dose dependent protection against maximal electroshock- and pentylenetetrazole (PTZ)- induced seizure; demonstrated synergistic effect when co-administered with fluphenamic acid; and produced significant (p < 0.05) decrease in seizure progression in PTZ-kindled rats. DCP23 and DCP25 reduced sodium currents at different channel states in a concentration dependant manner. The results of this study showed that the compounds possess anticonvulsant effects and reduced the inward sodium currents. Therefore, they could exert anticonvulsant activity via sodium channels blockade.

Keywords:

• Voltage-gated sodium channels
• Anticonvulsant
• Dichloroanilines
• Kindling
• Maximal electroshock

Acknowledgements

We appreciate Tertiary Education Trust Fund through Ahmadu Bello University, Zaria (TETfund-ABU) for providing full travel grant to the United States of America. Also, we appreciate Patel Laboratory, Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA, for the technical assistance, provision of consumables and equipment.