Proton speciation and microspeciation of vinpocetine and related compoundsin aqueous and biomimetic media

Purpose. The determination of protonation macroconstants of twelve compound s in the vincamine drug family and the determination of protonation microco nstants of cis- and trans-apovincaminic acid in media of various solvent co mposition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms. Methods. UV-pH titrations have been used to determine the protonation macro constants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapola tion was applied to obtain aqueous logK values for compounds sparingly solu ble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group. Results. In the case of the two water-soluble compounds the extrapolated an d the directly measured aqueous logK values were in good agreement, verifyi ng all other extrapolated data. Compounds of cis-D/E ring anellation are 0. 4-0.8 logK units more basic than their epimeric, trans counterparts. The pH -dependent distribution of apovincaminic acid microspecies in aqueous and m embrane-like media is depicted in microspeciation diagrams. Conclusions. The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-DIE ring anellation eburnanes than in cis ones, as reflected by t he protonation constants. Solvent-dependent basicity data predict superiori ty of trans isomers in lipophilicity and membrane-penetrating ability.