Preclinical evaluation of anticonvulsant activity of N-(p-aminobenzoyl)-1,2,3,4-tetrahydroquinoline

Abstract

Anticonvulsant activity of N-(p-aminobenzoyl)-1,2,3,4- tetrahydro-quinoline (NTQ), a newly synthesized ameltolide analog, was investigated with regards to efficacy and toxicity in mice. Additionally, its effect on NMDA receptors was also performed on NR1a/NR2B expressed in Xenopus oocytes. NTQ, given intraperitoneally, was able to protect the animals in both maximal electroshock seizure and pentylenetetrazole (PTZ) tests, while ameltolide was effective only in the MES. NTQ was less potent than ameltolide, exhibiting the median effective dose (ED50) of 13.33 mg/kg body weight (B.W.), whereas the corresponding value of ameltolide was 0.96 mg/kg B.W. Ameltolide seemed to possess better safety profile than NTQ as indicated by the relative safety margin (LD50/ED50) of 65.28 for ameltolide and 44.97 for NTQ. Furthermore, based on the finding that the median neurotoxic dose (TD50) established by rotarod test was 37.28 and 7.18 mg/kg B.W. for ameltolide and NTQ respectively, ameltolide appeared to have more favorable protective index (TD50/ED50) than NTQ. Further experiment using Xenopus oocyte with NMDA receptor composing of NR1a and NR2B subunits was performed to probe for the effect of NTQ and ameltolide on NMDA-induced current. While NTQ and ameltolide did not induce any changes in current or a shift in membrane potential of oocyte, both of them significantly inhibited NMDA-induced current demonstrating the IC50 of 0.10 and 0.12 ?M respectively. Therefore, it is likely that inhibition of excitation of NMDA receptor may, at least in part, accounted for its anticonvulsant activity. In conclusion, the present study has identified NTQ as a broad-spectrum anticonvulsant agent, albeit its lower safety margin and protective index. Inhibition of NMDA receptor may partly contribute to anticonvulsant activity of these two compounds. Further structural modification of NTQ to improve its safety while preserving a broad-spectrum anticonvulsant activity should be carried out.