Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys.

1. J Pharmacol Exp Ther. 2004 Nov;311(2):770-7. Epub 2004 Jun 29.

Effect of the D3 dopamine receptor partial agonist BP897
[N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on
L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel
monkeys.

Hsu A(1), Togasaki DM, Bezard E, Sokoloff P, Langston JW, Di Monte DA, Quik M.

Author information:
(1)The Parkinson’s Institute, 1170 Morse Ave, Sunnyvale, CA 94089, USA.

Although l-3,4-dihydroxyphenylalanine (L-dopa) is one of the most effective
therapies for Parkinson’s disease, continued treatment may result in excessive
involuntary movements known as L-dopa-induced dyskinesias (LIDs). Because LIDs
can become dose-limiting, there is great interest in finding ways to ameliorate
or prevent this troubling side effect of L-dopa therapy. It was recently reported
that the D3 receptor partial agonist BP897
[N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] reduces LIDs without
diminishing antiparkinsonian effects of L-dopa in macaques. In the present study,
we tested the effects of BP897 on LIDs in squirrel monkeys, a nonhuman primate
particularly prone to dyskinesias. Parkinsonism was induced using
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were then gavaged with
L-dopa/carbidopa (7.5 or 15 mg/kg/dose) without and with BP897. The effects of
BP897 treatment were evaluated on several components of LIDs, including time
course, peak dyskinesias, and area under the curve (AUC), a measure that
encompasses both peak and duration of the response. Analyses of the time course
and overall dyskinetic response (AUC) showed that BP897 significantly reduced
LIDs but at the expense of the antiparkinsonian effect of L-dopa. BP897 had no
significant effect on peak dyskinesias. Correlation studies showed that
beneficial effects of BP897 on dyskinesias were linked to a decline in the
antiparkinsonian action of L-dopa. Analyses of a subgroup of animals with
mild/moderate parkinsonism yielded comparable results. Thus, in squirrel monkeys
in contrast to macaques, BP897 fails to exert an antidyskinetic effect without
diminishing the antiparkinsonian effects of L-dopa. These results suggest that
BP897 may be less effective than originally anticipated for treating LIDs in
Parkinson’s disease.

DOI: 10.1124/jpet.104.071142
PMID: 15226382 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus