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

Abstract

The purpose of the present study was to investigate anticonvulsant effect of N- (p-aminobenzoyl)-l ,2,3,4-tetrahydro- 4-methylquinoline(CU-17-06), a newly synthesized ameltolide analog, with regards to efficacy, lethality, and neurotoxicity. In addition, in vivo microdialysis experiments on freely moving rats were also performed in search for the possible effects of CU- 17-06 on cortical amino acid neurotransmitters that may underlie its anticonvulsant activity. CU-17-06 and ameltolide were able to protect the experimental animals exclusively in Maximal Electroshock Seizure (MES) but not in Pentylenetetrazol (PTZ) test. When given by an intraperitoneal route in mice. CU-17-06 was less potent than ameltolide. exhibiting the median effective dose (ED₅₀) of 77.62 mg/kg body weight (B.W.) whereas the corresponding value for ameltolide was 1.08 mg/kg B.W. Both compounds exhibited protection against MES at least 6 hours after dosing, however, with an increment of the ED₅₀ values. In term of safety. CU-17-06 seems to be rather safe as indicated by no lethality was observed in the dose up to 1,000 mg/kg B.W. whereas ameltolide demonstrated the LD₅₀ of 63 mg/kg B.W. The median neurotoxic dose (TD₅₀) of CU-17-06 established by Rotarod test. was 320 mg/kg B.W. while it was 9 mg/kg B.W. for ameltolide. Consequently the protective index (Pl= TD₅₀/ ED₅₀) of CU-17-06 was less favorable than that of ameltolide (4.16 and 9 respectively), implying that therapeutic dose of CU-17-06 should produce more pronounced motor impairment than that of ameltolide However both of them seem to be clinically safe. In microdialysis studies. It was found that neither CU-17-06 nor ameltolide was able to exert any significant effects on the level of cortical brain ammo acid (aspartate, glutamate, glycine and GABA). In conclusion, the present studies demonstrated rather similar profile of anticonvulsant activity between CU-17-06 and its parent compound, ameltolide. Therapeutic dose of CU-17-06 or ameltolide was anticipated to produce acceptable neurological unwanted effect. Furthermore. CU-17-06 was rather safe. Based on similarity in pharmacological screening profile and no changes on the level of brain amino acid neurotransmitters was observed after the administration of either CU-17-06 or ameltolide, it is suggestive that these two compounds may possess similar mechanism underlying anticonvulsant activity observed in experimental animals. Further structural modification of CU-17-06 may lead to the discovery of new ameltolide analogs with more favorable pharmacological and toxicological properties.