Abstracts

RATIONALE: Antiepileptic QSAR has been compromised by lack of good experimental models. We are studying the DHP class of compounds because in vitro pharmacologic data are readily available, representing activity at the calcium L-channel. We are hopeful that QSAR derived using DHP antagonist activities might be useful in understanding antiepileptic QSAR. METHODS: We have applied a variety of computational methods in the acquisition of our independent variables (InVar). Molecular dynamics was used to study the nature of the calcium interaction with each of 43 DHP analogues. Density functional theory and AM1 were used to obtain quantum mechanical descriptors. Spatial and thermodynamic descriptors were obtained using other modules included in cerius2 (MSI, Inc.). Cluster and multiple regression analysis were used to derive models. RESULTS: We found significant, strong correlations between the calcium antagonist activity of many of the DHP compounds and a single complex InVar, "[(LogP)(?-?)]." The LogP term is a measure of lipophilicity. The term "?" represents the energy difference between the highest occupied molecular orbital (HOMO) and the lowest empty molecular orbital (LEMO) for the state in which the DHP's are complexed with calcium (a ?-cation interaction with the substituted phenyl ring). The term "?" represents the same energy difference, but for the state in which the DHP's are not complexed with calcium. However, the data are not homogenous. There appear to be four clusters, two of which produce superb equations with "[(LogP)(?-?)]." The four basic equations are: (1)Log1/C=2.68-(.83)[(LogP)(?-?)], r?2=.96, P?.00000; (2)Log1/C=.02-(1.03)[(LogP)(?-?)], r?2=.99, P?.00000; (3)Log1/C=8.54+(.2)[(LogP)(?-?)], r?2=.69, P?.0004; and (4)Log1/C=6.8+(.24)[(LogP)(?-?)], r?2=.69, P?.006. Clusters can be combined and a term added which represents the volume of the substituent at the phenyl para position, and the latter two equations can be improved. CONCLUSIONS: We believe that these data may help to corroborate an electron-transfer mechanism in the action of DHP analogues as calcium channel antagonists.