Orally active carbamate prodrugs of the selective dopamine agonist N-0437: in-vivo activities in the 6-OHDA turning model and in-vitro activities.
The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11-15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37 degrees C, while the other test compounds were hydrolysed relatively slowly, with t1/2 values ranging from 1.5-6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1-12 times more lipophilic than N-0437). The potential cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak cholinesterase inhibitors.
Department of Medicinal Chemistry, University Centre for Pharmacy, Groningen, The Netherlands.
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den Daas
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de Boer
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Tepper
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Rollema
A S
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Horn
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002219:Carbamates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015259:Dopamine Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D006892:Hydroxydopamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D015259:Dopamine Agents; D006892:Hydroxydopamines; D011355:Prodrugs; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; D016627:Oxidopamine