Fiakpui C Y, Namchuk M N, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Drug Des Deliv. 1990 Jun;6(2):111-21.
3-Alkoxycarbonylaminomethylcarbonylamino-4-(arylcarbonyl)pyr idines--in which the chlorophenyl ring of dipeptidylaminobenzophenones is replaced by a pyridyl ring--were synthesized and evaluated as anticonvulsants using subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizure screening tests. The substituent on the aryl ring of the 4-arylcarbonyl moiety was a determinant of activity in both tests, the potency order of substituents being generally 2-F greater than 2-H greater than 2-Cl. Compounds possessing a 3-benzyloxycarbonylaminomethylcarbonylamino substituent exhibited moderate activity in the scPTZ test, whereas all 3-tert-butoxycarbonylaminomethylcarbonylamino derivatives were inactive. The test results in the scPTZ screen suggest that the 3-benzyloxycarbonylaminomethylcarbonyl(N-methyl)amino compounds may undergo biotransformation, at least in part, to pyrido[3,4-e]-1,4-diazepin-2-ones. 3-Alkoxycarbonylaminomethylcarbonyl(N-methyl)amino-substituted compounds were always more potent than analogous 3-alkoxycarbonylaminomethylcarbonylamino-substituted compounds in the scPTZ test, whereas they were equipotent in the MES screen. Following oral administration, 3-benzyloxycarbonylaminomethylcarbonyl(N-methyl)amino-4-(2-chlorob enzoyl) pyridine exhibited a potency greater than that of valproic acid but less than that of clonazepam in the rat scPTZ screening test. 3-Benzyloxycarbonylaminomethylcarbonylamino-4-(2-fluorobenzoyl)pyr idine was the most potent compound in the rat oral MES screening test, exhibiting an activity greater than that of clonazepam but less than that of phenytoin. The 3-alkoxycarbonylaminomethylcarbonylamino-4-(arylcarbonylpyridin es had moderate affinity for the benzodiazepine receptor site(s); the IC50s in displacing 10 nM [3H]flunitazepam were in the 0.37-15.11 microM range (clonazepam = 0.003 microM).
3-烷氧羰基氨基甲基羰基氨基-4-（芳基羰基）吡啶（其中二肽基氨基二苯甲酮的氯苯环被吡啶环取代）被合成出来，并使用皮下注射戊四氮（scPTZ）和最大电休克（MES）诱导惊厥筛选试验对其作为抗惊厥剂进行了评估。4-芳基羰基部分芳环上的取代基是两种试验中活性的决定因素，取代基的效力顺序通常为2-氟大于2-氢大于2-氯。具有3-苄氧羰基氨基甲基羰基氨基取代基的化合物在scPTZ试验中表现出中等活性，而所有3-叔丁氧羰基氨基甲基羰基氨基衍生物均无活性。scPTZ筛选试验的结果表明，3-苄氧羰基氨基甲基羰基（N-甲基）氨基化合物可能至少部分地发生生物转化为吡啶并[3,4-e]-1,4-二氮杂卓-2-酮。在scPTZ试验中，3-烷氧羰基氨基甲基羰基（N-甲基）氨基取代的化合物总是比类似的3-烷氧羰基氨基甲基羰基氨基取代的化合物更有效，而它们在MES筛选中效力相当。口服给药后，3-苄氧羰基氨基甲基羰基（N-甲基）氨基-4-（2-氯苯甲酰基）吡啶在大鼠scPTZ筛选试验中表现出的效力大于丙戊酸但小于氯硝西泮。3-苄氧羰基氨基甲基羰基氨基-4-（2-氟苯甲酰基）吡啶是大鼠口服MES筛选试验中最有效的化合物，其活性大于氯硝西泮但小于苯妥英。3-烷氧羰基氨基甲基羰基氨基-4-（芳基羰基）吡啶对苯二氮䓬受体位点具有中等亲和力；取代10 nM [3H]氟硝西泮的IC50在0.37 - 15.11 microM范围内（氯硝西泮 = 0.003 microM）。
