Synthesis and investigation of novel shelf-stable, brain-specific chemical delivery system

Abstract

A 1,4-dihydropyridine pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs into the brain. Monoamine oxidase inhibitors (MAOIs) were used as a model example to be delivered into the brain. Chemical and biological oxidations of these compounds were investigated. The prepared 1,4-dihydropyridines were subjected to various chemical and biological oxidation to evaluate their ability to cross blood brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. 1-(Ethoxy-carbonylmethyl)-3,5-bis[N-(2-fluorobenzylideneamino) carbamoyl]-1,4-dihydropyridine (31) proved to cross BBB in adequate rate and converted by the oxidizing enzymes into the corresponding quaternary salt N-(ethoxycarbonylmethyl)-3,5-bis[N-(2-fluorobenzylideneamino)carbamoyl]pyridinium bromide (20). Stability studies of the synthesized chemical delivery systems (CDSs) at various pH values and temperatures showed that the shelf life time of a solution containing compound 31 is 20.53 days at 5°C, which recommend a lower storage temperature for such solutions. The prepared CDSs proved to be fairly stable for powder form storage. The stability of the prepared compounds is attributed to the conjugation of the two carboxylic functions at C3 and C5 of the pyridine ring with their adjacent double bonds. These results are in consistency with the original rationale design