PubMedDate not supplied
In mice, the diethylglycineamide analogue of LY201116, DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide), is metabolized by consecutive N-deethylations for form MEGA and GA; the monoethylglycineamide and glycineamide analogues of LY201116, respectively. All of these compounds are in turn hydrolyzed to form LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide]. LY201116 is N-acetylated to form the N-acetyl metabolite, NAC. NAC is also deacetylated to reform LY201116. All of the above compounds inhibit maximal electroshock-induced seizures (MES) in mice. After oral administration, the potencies of these compounds were similar at their time of peak anticonvulsant effect. However, the MES ED50 values for the above compounds 5 min after iv dosing were 43, 13, 2, and 0.5 mg/kg for DEGA, MEGA, GA, and LY201116, respectively. Similar plasma levels of LY201116 were produced in mice 5 min after iv dosing with the respective ED50 values of the above compounds, which suggested that all of the compounds produced their anticonvulsant effects via LY201116. The in vivo metabolism of DEGA and MEGA but not GA to LY201116 was inhibited by the acylamidase inhibitor bis-(p-nitrophenyl) phosphate (BNPP). Mice predosed with BNPP were not protected by DEGA and MEGA from MES-induced seizures and the plasma samples contained little or no LY201116. The metabolism of GA to LY201116 was not inhibited by BNPP, and GA was an active anticonvulsant in BNPP-pretreated mice. The apparent iv potency of DEGA increased dramatically with time after dosing, again suggesting time-dependent, metabolically mediated liberation of the more potent anticonvulsant LY201116.