Evaluation of mono- and dibenzoyl esters of dopamine as potential pro-drugs for dopamine in the central nervous system

Shanaz M. Tejani-Butt, Miroslawa Hauptmann, Anil D'Mello, Alan Frazer, Jill M. Marcoccia, David J. Brunswick

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

In this study, two ester pro-drugs of dopamine (DA) were synthesized and evaluated. These derivatives were the monobenzoyl (MBDA) and dibenzoyl (DBDA) esters of DA. MBDA was 300-fold and DBDA was 20,000-fold more lipophilic than DA itself. The half-lives of hydrolysis for MBDA and DBDA at physiologic pH and temperature were 15 and 420 min respectively. These compounds were radiolabelled and their uptake into brain measured. 14C-DBDA penetrated the brain rapidly; 0.28% of the dose injected was taken up per gram of brain tissue at 5 min. However DBDA did not produce measurable increases in DA levels in the brain. 14C-MBDA was found not to penetrate the brain. However, when MBDA was administered intracerebroventricularly (i.c.v.) to rats, it caused DOPAC levels to increase significantly both in the striatum and in the rest of the brain. The increase in the amount of DOPAC measured in the striatum was 3 to 10-fold greater than that seen in the rest of the brain. In rats that were pretreated with the MAO inhibitor, pargyline, MBDA given i.c.v. caused increases in DA levels in both the striatum and in the rest of the brain. The increased DA levels in striatum were considerably greater than those seen in the rest of the brain. From these results, it is inferred that MBDA is being hydrolyzed in vivo in the brain to form DA which is then taken up into dopaminergic neurons. Given this, it seems likely that an ester pro-drug of DA can be obtained that will have sufficient lipophilicity to penetrate the brain as well as a rate of hydrolysis that will produce increases in DA in the brain.

Original languageEnglish (US)
Pages (from-to)497-503
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume338
Issue number5
DOIs
StatePublished - Nov 1988
Externally publishedYes

Keywords

  • Dibenzoyldopamine
  • Hydrolysis
  • Lipophilicity
  • Monobenzoyldopamine
  • Pro-drug

ASJC Scopus subject areas

  • Pharmacology

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