L-dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease.
Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006892:Hydroxydopamines / Q000633:toxicity; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009069:Movement Disorders / Q000139:chemically induced / Q000188:drug therapy; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
D006892:Hydroxydopamines; D007980:Levodopa; D012110:Reserpine; D016627:Oxidopamine