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  • 1
    Electronic Resource
    Electronic Resource
    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 (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 341 (1990), S. 186-191 
    Details
    ISSN: 1432-1912
    Keywords: Prodrugs ; 6-OHDA ; N-0437 ; Bioavailability ; Dopamine agonist
    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 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169729
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  • 2
    Electronic Resource
    Electronic Resource
    Transdermal administration of the dopamine agonist N-0437 and seven ester prodrugs: comparison with oral administration in the 6-OHDA turning model (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 655-659 
    Details
    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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  • 3
    Electronic Resource
    Electronic Resource
    Effect of dihydroxy-2-aminotetralin derivatives on dopamine metabolism in the rat striatum (1980)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 310 (1980), S. 219-225 
    Details
    ISSN: 1432-1912
    Keywords: Dihydroxyaminotetralins ; Apomorphine ; Prodrugs ; Striatum ; Dopamine metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in the striatum of rats after i.p. injection of apomorphine, N,N-dipropyldopamine and a series of alkylated and/or esterified dopamine analogues of the dihydroxyaminotetralin type. All compounds tested caused a decrease in DOPAC- and HVA-concentrations. The N-alkylated derivatives had a rapid onset of action, showing a maximal HVA decrease after 15–45 min, after which time the metabolite concentrations slowly returned to control values. In addition, the dihydroxyaminotetralins, especially N,N-dipropylamino-5,6-dihydroxytetrahydronaphthalene (DiPr-5,6-ADTN), produced a rapid, short lasting elevation of DA concentrations. The esterified primary amines, dibenzoyl-5,6-and dibenzoyl-6,7-dihydroxyaminotetralin, had a delayed effect, causing a maximal HVA decrease after 4–6 h. DiPr-5,6-ADTN was found to be the most potent compound, with a maximal effect at a dose of 0.33 μmol/kg, it being 30 times more potent than apomorphine and DiPr-6,7-ADTN. The results corroborate reported behavioural data, and the relative potencies of the alkylated derivatives in this test system for dopaminergic activity are in agreement with those based on stereotyped behaviour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00499913
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacological profile of non-hydroxylated and ether derivatives of the potent D2-selective agonist N-0437 (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 343 (1991), S. 134-142 
    Details
    ISSN: 1432-1912
    Keywords: Aminotetralins ; Dopamine agonist ; Microdialysis ; 6-Hydroxydopamine ; Prodrugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Derivatives of the potent dopamine D2-selective agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) were designed, aimed at producing drugs with less sensitivity towards metabolic inactivation (in particular glucuronidation at the 5-OH position). Since aminotetralins with a 5-methoxy substituent or lacking the 5-hydroxy group have been reported to retain dopaminergic activity, the non-5-hydroxylated N-0437 (N-0918) and two ethers of N-0437 [5-methoxyN-0437 (N-0724) and 5-cyclopentoxy-N-0437 (N-0953)] have been prepared and tested. Three indices for activity at central dopamine receptors are considered: (1) the displacement of (3 H)-SCH-23390 and (3H)-spiperone from calf caudate membranes, (2) the effects on dopamine release and metabolism in the striatum of freely moving rats after systemic and intrastriatal administration as assessed by brain microdialysis, and (3) the ability to elicit contralateral turning in rats with a unilateral 6-OH-dopamine lesion of the nigrostriatal pathway. In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured. The results show the necessity of the 5-OH group for direct dopaminergic activity: N-0918, N-0724 and N-0953 are all inactive after intrastriatal administration in the microdialysis model and all three drugs show a weak in vitro affinity for both D1 and D2 receptors. Although N-0918 is also inactive after systemic administration in the microdialysis and turning model, N-0724 and N-0953 do exhibit dopaminergic activity after systemic administration in these models. Because of the in vivo formation of N-0437 after N-0724 and N-0953 administration, it is hypothesized that this dopaminergic activity is the result of metabolic activation. The cyclopentoxy group (present in N-0953) then appears to be an interesting prodrug moiety because it seems to give rise to small (but sufficient) and constant N-0437 levels in the brain. Deceased January 2, 1990 Send offprint requests to J. M. Jansen at the above address
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168600
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  • 5
    Electronic Resource
    Electronic Resource
    Continuous production of the pharmaceutical 7,8-dihydroxy N-di-n-propyl 2-aminotetralin using a phenoloxidase from cell cultures of Mucuna pruriens (1990)
    Springer
    Plant cell, tissue and organ culture 23 (1990), S. 209-215 
    Details
    ISSN: 1573-5044
    Keywords: 2-aminotetralins ; bioconversion ; catechols ; continuous production ; Mucuna pruriens L. ; phenoloxidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Alginate-entrapped cells of Mucuna pruriens as well as the phenoloxidase isolated from the cell cultures, are able to ortho-hydroxylate several mono-, bi- and tri-cyclic monophenols. In this study, 7,8-dihydroxy N-di-n-propyl 2-aminotetralin, a catechol of pharmaceutical interest and difficult to prepare chemically, could be produced in considerable quantities by bioconversion of the precursor 7-hydroxy N-di-n-propyl 2-aminotetralin. A continuous flow system on a laboratory scale was used, which consisted of a phenoloxidase suspension in dialysis tubing as the biocatalysator in an airlift fermentor coupled with an aluminium oxide column for selective product isolation. Product formation continued for at least 50 h, resulting in ca. 130 mg product per liter, this being a bioconversion percentage of 25%. When the enzyme preparation was reused, 85% of the original activity was measured.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00034434
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