NB-355: a novel prodrug for L-DOPA with reduced risk for peak-dose dyskinesias in MPTP-treated squirrel monkeys

Abstract

Prodrugs may be used to improve the absorption and bioavailability of certain active compounds. We have examined the ability of a novel catechol monoester of L-DOPA, NB-355 [L-3-(3-hydroxy-4-pivaloxyloyphenyl)alanine], to stimulate locomotor activity and induce dyskinesias in MPTP-treated primates. In the presence of carbidopa, a dose-dependent increase in locomotor activity over 4 1/2 h was observed following administration of L-DOPA (10, 20 or 40 mg/kg p.o.) or NB-355 (20, 40 or 80 mg/kg p.o. dopa equivalent). The dose-response curve for NB-355 was shifted to the right such that approximately twice the dopa equivalent dose of NB-355 was required to stimulate locomotor activity to the same level observed for L-DOPA. At doses matched for total locomotor stimulation over the 4 1/2-h period (20 mg/kg L-DOPA and 40 mg/kg NB-355), there was a more gradual rise and increase in the duration of motor stimulation by approximately 40% using NB-355. At these doses, drug-induced dyskinesias were less severe following treatment with NB-355 than with L-DOPA. Our findings suggest that NB-355 may be a useful therapeutic agent for increasing the duration of action of L-DOPA and reducing the severity of peak-dose dyskinesia.