Structure-activity relationships of phenytoin-like anticonvulsant drugs.

Abstract

A limited series of compounds structurally related to phenytoin has been tested in the maximal electroshock seizure (MES) test in order to define the impact on their antiepileptic activity of reducing the ability to form a hydrogen bond. A net stepwise decrease of the anticonvulsant activity was observed when the hydantoin ring structure was altered into succinimide and pyrrolidinone and when these rings were N-methylated. The pharmacological data analyzed in terms of structure-activity relationships (SAR) indicate the importance of the capability of forming hydrogen bonds. Further insight into the molecular mode of action of phenytoin was gained by a 13C NMR study of three phenytoin analogues deuterated in one of the phenyl groups, i.e., o-, m-, p-deuteriophenytoin. This approach allowed the unambiguous assignment of the chemical shifts of the ortho, meta, para, and ipso carbons. Measurement of the T1 relaxation times provided a value of 0.2 s for the para carbon and 0.8 s for the meta and ortho carbons of the phenytoin phenyl rings. These data are consistent with the view that the two phenyl groups possess a certain degree of rotational freedom along the para-ipso axis. More generally, the present results, as well as some literature data, support the concept that the ability to form hydrogen bonds as well as a certain degree of motional freedom of the phenyl groups are important SAR features in antiepileptic phenytoin-like drugs.