Evaluation of anticonvulsant activity of N-(p-aminobenzoyl)-1,2,3,4-tetrahydro-4-methylquinoline

Abstract

Anticonvulsant activity of N-(p-aminobenzoyl)-1,2,3,4-tetrahydro-4-methylquinoline (NMQ), a newly synthesized ameltolide analogue, was investigated with regards to efficacy, lethality and neurotoxicity in mice. In vivo microdialysis experiments on freely moving rats were also performed in search for the possible effect of NMQ on cortical amino acid neurotransmitters. Similar to ameltolide, intraperitoneally given NMQ exerted it protective effect exclusively in maximal electroshock seizure (MES), but not in pentylenetetrazole test. However, in comparison with ameltolide which exhibited the median effective dose (ED50) of 1.08 mg/kg body weight (B.W.), NMQ was less effective (ED50 = 77.62 mg/kg B.W.). Based on the finding that no lethality was observed in mice being given NMQ up to 1000 mg/kg B.W. while the median lethality dose (LD50) of ameltolide was observed at 63 mg/kg B.W., NMQ appeared to be superior to ameltolide with regards to safety. The median neurotoxic dose (TD50) from the rotarod test was found to be 320 and 9 mg/kg B.W. for NMQ and ameltolide respectively, resulting in lower protective index (PI=TD50/ED50) of NMQ (4.12) than that of ameltolide (8.33). Thus, it could be anticipated that therapeutic dose of NMQ which seemed to be safe would produce more pronounced motor impairment than that of ameltolide. In microdialysis study on freely moving rats, it was found out that neither NMQ nor ameltolide was able to exert significant changes on the level of cortical brain amino acid neurotransmitters, namely, aspartate, glutamate, glycine and GABA. Therefore, some mechanisms other than alteration in brain amino acid neurotransmitters should underlie anticonvulsant activity exhibited by these two compounds in MES test. Furthermore, based on similarity in pharmacological screening profile of NMQ and ameltolide observed in the present study, it is suggestive that these two compounds may possess rather similar mechanism of action.