Document Detail

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.
MedLine Citation:
PMID:  1971427     Owner:  NLM     Status:  MEDLINE    
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.
I den Daas; P G Tepper; A S Horn
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  341     ISSN:  0028-1298     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  1990 Mar 
Date Detail:
Created Date:  1990-06-27     Completed Date:  1990-06-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  GERMANY, WEST    
Other Details:
Languages:  eng     Pagination:  186-91     Citation Subset:  IM    
University Centre for Pharmacy, State University of Groningen, The Netherlands.
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MeSH Terms
Behavior, Animal / drug effects
Biological Availability
Dopamine Agents / pharmacokinetics*
Dose-Response Relationship, Drug
Hydroxydopamines / pharmacology
Naphthalenes / pharmacokinetics*
Rats, Inbred Strains
Stereotaxic Techniques
Stereotyped Behavior / drug effects
Tetrahydronaphthalenes / pharmacokinetics*
Thiophenes / pharmacokinetics*
Reg. No./Substance:
0/Dopamine Agents; 0/Hydroxydopamines; 0/Naphthalenes; 0/Prodrugs; 0/Tetrahydronaphthalenes; 0/Thiophenes; 1199-18-4/Oxidopamine; 92206-54-7/N 0437

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