Emil Pop* Pages 279 - 294 ( 16 )
Several properties of 1,4-dihydropyridine pyridinium salt redox targetor-based brain specific chemical delivery systems (CDS), important for the efficient transport of xenobiotics to the brain, including lipophilicity, oxidative and hydrolytic stability and resistance to hydration can be influenced, modified and optimized by appropriate structural changes. These modifications which address the targetor and its linkage with the drug can be quite diverse and specific to particular properties. A higher lipophilicity of CDSs can be achieved, for example, by increasing the length of the N-alkyl substituent of the 1,4- · dihydropyridine moiety, by employing a dihydroisoquinoline- type carrier or by using complex linkages and spacers. The hydrolytic stability is dependant mainly on the type of linkage · between targetor and drug (ester, amide, carbamate, substituted carbamate, glycol diester, etc) while the stability toward oxidation and hydration are dependant on targeter and its substituents and type of linkage. Numerous examples of structural variations and their effect on properties of CDSs are given. Theoretical support, generated by molecular orbital calculations, is provided for some of these practical observations. Data presented are useful for the rational design of CDSs
*Presented at the 1-St Drug Optimization via Retrometabolism Conference, Amelia Island Plantation, FL, May 6-9, 1997.