Brain-specific chemical delivery systems for beta-lactam antibiotics. Synthesis and properties of some dihydropyridine and dihydroiosquinoline derivatives of benzylpenicillin.
Six chemical delivery systems (CDS) were synthesized for benzylpenicillin in order to improve its transport across the blood-brain barrier. The CDS's were based on a dihydropyridine----quaternary pyridinium ion redox system, analogous to the naturally occurring NADH----NAD+ system. Two different types of CDS's were prepared: benzylpenicillin esters of diols in which the other hydroxyl group is esterified by dihydrotrigonelline and benzylpenicillin esters of amino alcohols in which the amine group is acylated by dihydrotrigonelline, or by 1,2-dihydro-2-methyl-4-isoquinolinecarboxylic acid. Lipophilicities of the CDS's were proved to be much higher than those of benzylpenicillin by using Rm values as lipophilicity indexes. Upon oxidation, all of the CDS's gave the quaternary ion forms. Kinetic studies in buffer (pH profiles) indicated that the quaternary salts released benzylpenicillin in pH range of 5-9 via hydrolysis. The CDS's in acidic media yielded as the major reaction product 6-hydroxy-1,4,5,6-tetrahydropyridines as a result of water addition, while in basic conditions benzylpenicillin was released. The water addition reaction was dependent on the CDS's structure, being more prevalent in the case of the "amide-esters". The dihydroisoquinoline CDS was rather stable in the pH range 5-8.
Center for Drug Design and Delivery, J. Hillis Miller Health Center, University of Florida, Gainesville 32610.
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D001812:Blood-Brain Barrier; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010400:Penicillin G / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics
D004095:Dihydropyridines; D007546:Isoquinolines; D011355:Prodrugs; D010400:Penicillin G