To investigate anticonvulsant effect of N-(p-aminobenzoyl)-1,2,3,4- tetrahydronquinoline (NTQ), a newly synthesized ameltolide analog, with regards to efficacy, acute toxicity, neurotoxicity and some other effects on the central nervous system (CNS). In addition, Xenopus laevis expressing system was used to examine the possible pharmacological properties of the test substances on the NMDA receptors expressed in Xenopus laevis oocytes injected with mRNA. While NTQ was effective in both Maximal Electroshock Seizure (MES) and Pentylenetetrazole (PTZ) test, ameltolide was exclusively effective in the MES but not PTZ test. When given by an intraperitoneal route in mice, NTQ was less potent than ameltolide, exhibiting the median effective dose (ED[subscript 50]) of 13.33 mg/kg body weight (B.W.) whereas the corresponding value for ameltolide was 0.96 mg/kg B.W. Both compounds exhibited protection against MES at least 9 hours after dosing, however, with an increment of the ED[subscript 50] values. In terms of safety, ameltolide seems to be safer than NTQ as indicated by the relative safety margin (LD[subscript 50]/ED[subscript 50] of 65.28 for ameltolide and 44.97 for NTQ. The median neurotoxic dose (TD[subscript 50]) established by Rotorod test, were 37.28 and 7.18 mg/kg B.W. for NTQ and ameltolide, respectively.
Thus ameltolide seems to possess more favorable protective index (PI = TD[subscript 50]/ED[subscript 50]) than that of NTQ. However, based on the results of locomotor activity and potentiation of barbiturate sleeping time tests, NTQ is preferably expected to exert a minor degree of CNS depression in its effective dose. Xenopus oocyte with NMDA receptor composing of NR1a and NR2B subunits was used to probe the effect of NTQ and ameltolide on NMDA-induced current. While NTQ and ameltolide did not induce either current or a shift in membrane potential of oocyte, both of them significantly inhibited NMDA-induced current demonstrating IC[subscript 50] of 0.10 and 0.12 micro-M, respectively. Therefore, it is likely that inhibition of excitation of NMDA receptor may, at least in part, accounted for anticonvulsant activity in animal models of both NTQ and ameltolide, though, precise mechanism of action remains unknown. In conclusion, the present study indentified NTQ as a broad spectrum anticonvulsant agent with lower safety margin and lower protective index than those exerted by ameltolide. However in its effective dose, NTQ is expected to produce less unwanted effect regarding CNS depression. Inhibition of excitation of NMDA receptor (NR1a/NR2B) may explain anticonvulsant effect exhibited by ameltolide and NTQ in animal models. Further structural modification of NTQ to improve its safety profile while preserving broad spectrum property may lead to a discovery of new ameltolide analogs with favorable pharmacological and toxicological properties.