Improved Anticonvulsant Activity of Phenytoin by a Redox Brain Delivery System I: Synthesis and Some Properties of the Dihydropyridine Derivatives

Abstract

Nine chemical delivery systems (CDSs) were synthesized for the efficient transport of phenytoin (DPH) across the blood-brain barrier. The CDSs were based on a dihydropyridine ⇆ quaternary pyridinium ion redox system which relies on chemistry similar to the NADH ⇆ NAD interconversion for activity. The chemical carriers, derivatives of trigonelline, 1 -alkylcarboxynicotinamide, 3-pyridylacetic acid, and N-methylpicolinic acid, were esterified with 3-(hydroxymethyl)phenytoin. The CDSs proved to be more lipophilic (5–23 times) than DPH. The 1-alkylcarboxydihydronicotinamide CDSs, excluding the sterically hindered one (11e), were quite unstable in rat tissue homogenates and hydrolyzed to release DPH. In human blood, however, they were found to be much more stable (75 times) toward hydrolysis. All other CDSs were oxidized quantitatively to the corresponding pyridinium ion in rat brain homogenates. These compounds were found to possess the required physicochemical characteristics for delivering DPH into rat brain.