Orally Active Carbamate Prodrugs of the Selective Dopamine Agonist N-0437: In-vivo Activities in the 6-OHDA Turning Model and In-vitro Activities

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Abstract
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°C, while the other test compounds were hydrolysed relatively slowly, with t 1/2 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.

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