title: Improvement of the oral bioavailability of the selective dopamine agonist N-0437 in rats: the in vitro and in vivo activity of eight ester prodrugs.
abstract: 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.
authors.affiliation: University Centre for Pharmacy, State University of Groningen, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: den Daas
authors.forename: P G
authors.initials: PG
authors.lastname: Tepper
authors.forename: A S
authors.initials: AS
authors.lastname: Horn
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006868:Hydrolysis; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000493:pharmacokinetics*; D016627:Oxidopamine; D011355:Prodrugs; D051381:Rats; D011919:Rats, Inbred Strains; D013238:Stereotaxic Techniques; D013239:Stereotyped Behavior / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000493:pharmacokinetics*
chemical_list: D015259:Dopamine Agents; D006892:Hydroxydopamines; D009281:Naphthalenes; D011355:Prodrugs; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; D016627:Oxidopamine