QUANTUM PHARMACOLOGICAL STUDIES APPLICABLE TO THE DESIGN OF ANTICONVULSANTS - THEORETICAL CONFORMATIONAL-ANALYSIS AND STRUCTURE-ACTIVITY STUDIES OF BARBITURATES

We report the first large-scale systematic quantitative structure-acti vity relationship (QSAR) study of barbiturates, correlating molecular structures with anticonvulsant activity. To achieve this QSAR study, w e devised a four-step strategy. In step 1, an optimal quantum mechanic al technique for determining the geometry and shape (conformation) of barbiturates was ascertained; this is the AM1 semiempirical molecular orbital method. In step 2, the AM1 method was used to optimize the str uctures and molecular properties of 48 barbiturates with varying antic onvulsant activity. In step 3, discriminant analysis and regression an alysis statistical calculations were used to correlate the molecular p roperties of the 48 analogues against maximal electroshock (MES) and s ubcutaneous metrazol (s.c.Met)-induced seizures. In step 4, the contri bution of molecular electostatic properties to barbiturate anticonvuls ant activity was further refined by quantum mechanical derived molecul ar electrostatic potential (MEP) maps. Using this four-step strategy, we defined the pharmacophore, the portion of a molecule responsible fo r bioactivity, for anti-MES and anti-s.c.Met activity. For anti-s.c.Me t activity, barbiturate lipophilicity and geometry are important consi derations; for anti-MES activity, barbiturate topologic and electronic properties have increased relevance.