AM1-BASED MODEL SYSTEM FOR ESTIMATION OF BRAIN BLOOD CONCENTRATION RATIOS/

Estimation of brain uptake of solutes and drugs would be useful in des igning novel therapeutic agents. Given the problems associated with fr agment-based models, including the need for strict additivity, we used AM1-derived molecular parameters in attempting to generate an equatio n for predicting the log of the brain-to-blood concentration ratios (l og B:B) for a collection of compounds. Sequential fitting of the data using 10 AM1-derived variables indicated that dipole generated the mos t predictive one-term equation, dipole and log P, the best two-paramet er system, dipole, log P, and molecular weight produced the optimal th ree-term model, and dipole, log P, molecular weight, and HOMO energy r esulted in the best four-parameter paradigm. These systems were statis tically similar to those generated using general solvation equations, but with the use of fewer parameters. An expanded parameter set may ge nerated models of even better predictability. (C) 1996 John Wiley & So ns, Inc.