Fiakpui C Y, Phillips O A, Murthy K S, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Drug Des Discov. 1993;10(1):45-55.
1,3-Dihydro-5-phenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-ones (6-21), in which the chlorophenyl ring of 7-chloro-1,4-benzodiazepin-2-ones is replaced by a pyridyl ring, were synthesized and evaluated as anticonvulsants using subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizure screening tests. Structure-activity correlations indicated that a halo substituent at the 2-position of a 5-phenyl moiety enhanced scPTZ, but decreased MES, activity; the N1-substituent was a determinant of activity where the relative potency order was Me > CH2CH2NEt2 > cyclopropylmethyl; and that a 3-Me or 3-OH substituent generally decreased activity. This 1,3-dihydro-5-phenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one class of compounds had moderate affinity for the benzodoazepine receptor relative to clonazepam. In the mouse Phase II scPTZ screen all compounds tested were less active than clonazepam but more active than valproic acid, and in the MES screen all compounds tested were less active than phenytoin but more active than either clonazepam or valproic acid.
