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.

• Authors: S J Tye, N M Rupniak, T Naruse, M Miyaji, S D Iversen
• Journal: Clinical neuropharmacology (Clin Neuropharmacol) Vol. 12 Issue 5 Pg. 393-403 (Oct 1989) ISSN: 0362-5664 [Print] United States
• PMID: 2611764 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Prodrugs
• L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine
• Levodopa
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (adverse effects)
• Animals
• Dose-Response Relationship, Drug
• Dyskinesia, Drug-Induced (etiology)
• Levodopa (adverse effects, analogs & derivatives, pharmacology)
• Motor Activity (drug effects)
• Parkinson Disease, Secondary (chemically induced)
• Prodrugs (adverse effects, pharmacology)
• Saimiri
• Time Factors