IMPROVEMENT OF THE ORAL BIOAVAILABILITY OF THE SELECTIVE DOPAMINE AGONIST N-0437 IN RATS - THE INVITRO AND INVIVO ACTIVITY OF 8 ESTER PRODRUGS

The potent and selective D2-agonist N-0437 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin undergoes considerable first-pass metabolism due to glucuronidation of the phenolic group after oral administration. In an attempt to improve the bioavailability, eight ester prodrugs of N-0437 were synthesized, i.e. the acetyl, isobutyryl, pivaloyl, benzoyl, 2-methylbenzoyl, 2-methoxybenzoyl, 2,4-dimethylbenzoyl and 2-aminobenzoyl analogues. To examine the hydrolysis rates of these compounds in vitro studies were performed in rat serum. The prodrugs showed a very diverse pattern of hydrolysis rates. The in vivo activities were determined by testing the prodrugs in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used to measure the activity of the compounds. By calculating the area under the curve (AUC), of the time-effect curves of the prodrugs, a significantly improved duration of action was found for those prodrugs which have a slow in vitro hydrolysis rate. However no significant differences in total activity of these slowly hydrolysing prodrugs compared with N-0437 could be demonstrated, although the 2-aminobenzoyl and the 2,4-dimethylbenzoyl derivatives show interesting behavioural profiles. In contrast the isobutyryl ester, a prodrug with a relatively rapid hydrolysis rate, gave an improvement of turning behaviour over the whole time course in comparison with N-0437. © 1990 Springer-Verlag.