On the origin of the lack of anticonvulsant activity of some valpromide derivatives

Abstract

Two closely related N-substituted valpromide derivatives: N-valproyl glycinamide and N-valproyl glycine are comparatively analyzed, the first of which is antiepileptic active whereas the second is not. The study is based on a conformational analysis using an AM1 Hamiltonian that not only search for the lower energy structures of each derivative but also for the energy involved in their mutual interconversion. Open structures have been compared with cyclic ones, the latter including those stabilized by either inter or intra molecular hydrogen bonds (dimers and monomers, respectively). H-bond formation has been also evaluated by means of ab initio G94(6–31+G(d,p)) calculations for a smaller system (N-formylglycine/glycinamide) modeling both vacuum and solvent conditions. The conformational and electronic characteristics of the open and cyclic monomers, as well as of the dimer N-valproyl glycinamide and N-valproyl glycine structures are discussed. On the basis of the results of their comparative analysis, we have redefined the pharmacophore previously proposed for N-substituted valpromides [Tasso, Bruno-Blanch, Estiu, Int. J. Quant. Chem. 65(6), 1107 (1997)], relaxing some of the associated requirements. The corrected model requires one carbon atom or any bioisosteric substituent in an anticlinal conformation relative to the aminic nitrogen of the amide moiety, in addition to one hydrogen atom that should be antiperiplanar to the carbonyl oxygen. This model offers an explanation to the different response of N-valproyl glycinamide and N-valproyl glycine against convulsion, which is based on conformational restrictions. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 70: 1127–1136, 1998