CHROMATOGRAPHIC MODELING OF INTERACTIONS BETWEEN MELANIN AND PHENOTHIAZINE AND DIBENZAZEPINE DRUGS

Differences in drug-melanin interactions were determined for 13 phenot hiazine neuroleptics and 2 dibenzazepine thymoleptics by means of high -performance liquid chromatography. The chromatographic column was pac ked with a stationary phase obtained by chemical immobilization of syn thetic L-dopa melanin on silica particles. For six phenothiazines the melanin-binding parameters were also determined by an ultrafiltration method. Correlation between measures of drug-melanin interaction deter mined chromatographically and by the standard slow-equilibrium method was significant, however moderate. The chromatographic method of asses sing interactions between drugs and melanin permitted reliable and qua ntitatively comparable data for representative series of solutes to be readily obtained. Such data were subjected to the analysis of quantit ative structure-retention relationships (QSRR). It was found that rete ntion of the agents on the immobilized melanin column could be describ ed by two-parameter regression equations comprising the energy of the lowest unoccupied molecular orbital and either the water-accessible su rface area of a drug molecule or its hydrophobicity parameter, determi ned chromatographically an an immobilized artificial membrane column. The QSRR equation derived allows for the estimation of melanin binding based on the structure of a compound candidate, and thus rationalizes predictions of potential toxicity of drugs or drug candidates.