ANTICONVULSANT STUDIES OF THREE SYNTHESIZED DICHLOROSUBSTITUTED PHENYL PROPANAMIDES AND THEIR ACTION ON VOLTAGE-GATED SODIUM CHANNELS (Nav1.6)
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Abstract
The field of antiepileptic drug development has become dynamic, affording many promising research opportunities. Continued efforts are being made in the development of antiepileptic drugs employing a range of strategies, including modification of the structures of existing drugs, targeting novel molecular substrates and non-mechanismbased drug screening. This research is aimed at conducting anticonvulsant studies on three synthesized dichloro-substituted phenyl propanamides. Isomers of 2,3- (DCP23)- 2,5- (DCP25) and 3,4- (DCP34) Dichloro-substituted Phenyl Propanamides were synthesized from acrylamide and dichloro-substituted anilines. The products were formed by an addition reaction according to Michael’s reaction. The physicochemical properties of the products were determined, and their structures were elucidated using standard analytical procedures; infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. The test compounds were evaluated for anticonvulsant effect in both acute and chronic animal models, via intraperitoneal (i.p.). In maximal electroshock test (MEST), the percentage protection offered by DCP23, DCP25 and DCP34, at 50 mg/kg, was 71.4%, 57.2% and 42.9% respectively. The middle dose (25 mg/kg) of the compounds offered protection of 42.9% (DCP23), 28.5% (DCP25) and 14.3% (DCP34), while the lowest dose (12.5 mg/kg) offered minimal / no protection. The highest dose (50 mg/kg) of DCP23, DCP25 and DCP34 used in pentylenetetrazole-induced seizure test, offered 66.7%, 66.7 and 0% protections against clonic seizures. Also, DCP23, at doses of 25 and 12.5 mg/kg, produced 16.7% protection while similar doses of DCP25 and DCP34 did not offer any protection. There was statistically significant difference in the mean onset of seizure exhibited by DCP23 at doses of 50 mg/kg (p<0.001) and 25 mg/kg (p<0.001). In 4-aminopyridine-induced seizure test, there was no protection offered by all the tested compounds, but DCP34 at doses of 50 mg/kg and 25 mg/kg viii exhibited statistically (p<0.05) significant difference in the onset of seizures. All test compounds did not offer protection in strychnine-induced seizure test. In Picrotoxininduced seizure test, DCP23 and DCP25 offered protection against clonic convulsion of 66.7% and 83.3% (50 mg/kg) respectively and 50.0% and 66.7% (25 mg/kg) respectively. There was no protection at 12.5 mg/kg. The medial effective dose (ED50) for DCP23, DCP25 and DCP34 using MEST was found to be 25.12, 39.81 and 44.67 mg/kg respectively, while that of picrotoxin was 35.48 mg/kg (DCP23) and 28.18 mg/kg (DCP25). The median toxic doses (TD50) were 100.0, 100.0 and 104.7 mg/kg for DCP23, DCP25 and DCP34 respectively. The protective index (MEST) was 3.98, 2.51 and 2.33 respectively while that of picrotoxin-induced seizure test was 2.82 (DCP23) and 3.55 (DCP25). In the single oral administration (100 mg/kg) evaluation, DCP23, DCP25 and DCP34 offered 37.5%, 50% and 0.0% protections respectively against tonic hind limb extension (THLE) while a 5-day administration offered higher protection of 50%, 75% and 25% respectively. Co-administration of DCP23 (50 mg/kg), DCP25 (50 mg/kg) and DCP34 (50 mg/kg) each with 5 mg/kg fluphenamic acid, resulted in potentiation as the percentage protection against THLE (MEST) were 100% for DCP23 and DCP25, and 50% for DCP34. When DCP23 and DCP25 at the doses of 25 mg/kg, were coadministered with nickel chloride (5 mg/kg) the percentage protection against PTZ-induced seizure were 66.67% and 33.33% respectively. Similarly, their coadministration produced significant (p<0.05) difference in the mean onset of seizure when compared with the control group. Cyproheptadine at the dose of 4 mg/kg did not affect the anticonvulsant effect of DCP23 (50 mg/kg) and DCP25 (50 mg/kg) against PTZ-induced seizure. DCP23 (50 mg/kg) and DCP25 (50 mg/kg), significantly (p<0.001) decreased the onset of sleep as well as increased the duration of sleep (p<0.05). All the compounds at the dose of 50 mg/kg significantly (p<0.05) reduced the ix severity of seizure episodes induced by kindling. A 28-day sub-chronic study was conducted for DCP25 at doses of 50, 25 and 12.5 mg/kg. The results showed that DCP25 at 50 mg/kg only, caused significant (p<0.05) increase in urea, creatinine and aspartate aminotransferase levels. There was no significant (p<0.05) change in haematological indices, lipid profile parameters as well as other renal and liver function test parameters caused by DCP25. The possible mechanism of action was studied on voltage-gated sodium channels(Nav1.6) at different states of the channel: DCP23 at holding potential of -60 mV, produced concentration-dependent tonic blockade of sodium current of 9.73%, 18.04%, 46.80%, 68.46%, 95.64 and 98.10% at 10µM, 30µM, 60µM, 100µM, 300µM and 600µM respectively. At holding potential of -60 mV, DCP25 at 100µM and 600µM blocked the current by 21.63% and 83.03%; while DCP34 (100µM and 600µM) blocked the current minimally by 3.8% and 16.9%, respectively. DCP23 was further tested at a holding potential of -100 mV at the graded concentration (10µM, 30µM, 60µM, 100µM, 300µM and 600µM) and similarly blocked the sodium currents by 0%, 10%, 28.93%, 50.12%, 88.51% and 90.10% respectively. The IC50 values of DCP23 were 64.76 and 100.37 µM at resting and inactivated states respectively. The activation/inactivation pattern in the presence of DCP23 (100 µM) indicated that there was significant reduction in the elicited current even at depolarized potential where the sodium conductance was found to be highest. The results obtained from this work showed that the compounds possess anticonvulsant effects mediated partly via voltage-gated sodium channel blockade.
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