L-dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice.
The intraperitoneal administration of L-dopa and a series of ester prodrugs of L-dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with L-dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following L-dopa administration. Overall the m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs produced greater elevations of striatal and tuberculum olfactorium HVA, but not DOPAC, compared with L-dopa. The administration of the 2-tetrahydropyranyl-methyl derivative only enhanced striatal HVA and striatal and tuberculum olfactorium DOPAC concentrations. Changes of HVA and DOPAC tissue concentrations following administration of the 2-hydroxypropyl, n-propyl, methyl, ethyl and 2-(1-methoxy)propyl ester prodrugs were comparable with those produced by the administration of L-dopa itself. The alterations in striatal and tuberculum olfactorium HVA and DOPAC levels observed did not correlate with the ability of these compounds to elicit locomotor activity in reserpinized mice.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D012110:Reserpine / Q000494:pharmacology*
D004364:Pharmaceutical Preparations; D011355:Prodrugs; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D012110:Reserpine; D004298:Dopamine; D006719:Homovanillic Acid