Conformational analysis of convulsant and anticonvulsant barbiturates

In an effort to obtain definitive structure‐activity relationships for the convulsant and anticonvulsant barbiturates a theoretical and experimental study was undertaken of the molecular conformations of 16 optical, geometric, and structural isomers of pentobarbitone and its homologues, four of which are convulsant. Initially classical calculations were used to obtain approximate potential energy surfaces, including quantitative estimates of barriers and the locations of energy minima. The latter conformations were further refined by minimizing total energy with respect to all geometric variables using mindo/3. Quantitative agreement between the classical and quantum mechanical calculations was generally good. The rotational barriers between low energy conformations were higher than expected, suggesting that barbiturates may be conformationally restricted even at physiological temperatures. This was confirmed by 1 H and 13 C nuclear magnetic resonance. In each case the observed solution conformations fell within minimum energy regions on the calculated potential energy surfaces. For the purpose of correlating conformation with biological activity we did not assume that the lowest energy gas phase or solution conformations were active, but included all energy minima within 10 kcal/mole of the global minimum. Only two conformations were thermally accessible to all the convulsants studied. Of these, the lower energy conformation bears a close structural resemblance, in key regions, to the potent natural convulsant picrotoxinin, with which the convulsant barbiturates may therefore share a common site of action.