Enol esters as potential prodrugs. IV. Enhanced delivery of the quaternary species coralyne to rat brain using 6′-acetylpapaverin and its enol esters as prodrugs☆

Abstract Coralyne (I), 6'-acetylpapaverin (II) and three 6'-acetylpapverin enol esters (acetate, IIIa; isobutyrate, IIIb; and pivalate, IIIc) were compared for their ability to deliver the cytotoxic quaternary coralyne ion to the brains of rats following i.v. administration. Maximum levels of coralyne were achieved in all cases within one hour of dosing and remained essentially constant for up to 90 h, indicating an inability of the quaternary ion to escape from the brain. The brain levels achieved decreased in the following order; II > IIIa , IIIb > IIIc > I , with II and IIIa producing ~ 60- and ~ 30-fold greater brain coralyne levels than achieved when I was administered. Based on the results obtained and previous work it appears that the determining factor in the accumulation of coralyne in brain following administration of the enol esters is the rate of production of II in the general circulation and not the rate of hydrolysis in brain tissue. Additionally, this study has demonstrated the utility of selected enol esters as prodrugs.