ISSN:
1432-1912
Keywords:
Prodrugs
;
Transdermal
;
Oral
;
6-OHDA
;
N-0437
;
Dopamine agonists
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were synthesized, i. e. the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-aminophenyl-, 2-methoxy-phenyl- and 2,4-dimethylphenylanalogues. In vivo activities were assessed by measuring contralateral turning after transdermal administration of N-0437 and its prodrugs to rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. From time-effect curves the area under the curve for separate time intervals was taken as a measure of dopaminergic activity during that interval. It was found that slowly hydrolyzing prodrugs, which are known to show an improved duration of action after oral administration, are devoid of activity after transdermal application. The acetyl-, the propionyl-and the isobutyryl analogues, which are prodrugs with a relatively high hydrolysis rate, were found to have interesting and promising profiles following transdermal application.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00175708
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