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Research ArticleBEHAVIORAL PHARMACOLOGY

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

Albert Hsu, Daniel M. Togasaki, Erwan Bezard, Pierre Sokoloff, J. William Langston, Donato A. Di Monte and Maryka Quik
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 770-777; DOI: https://doi.org/10.1124/jpet.104.071142
Albert Hsu
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Daniel M. Togasaki
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Erwan Bezard
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Pierre Sokoloff
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J. William Langston
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Donato A. Di Monte
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Maryka Quik
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Abstract

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.

Footnotes

  • This study was supported by Grant NS34886 from the National Institute of Neurological Disorders and Stroke.

  • doi:10.1124/jpet.104.071142.

  • ABBREVIATIONS:l-dopa, l-3,4-dihydroxyphenylalanine; LID, l-dopa-induced dyskinesia; BP897, N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ANOVA, analysis of variance; AUC, area under the curve.

    • Received May 19, 2004.
    • Accepted June 29, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
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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
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Research ArticleBEHAVIORAL PHARMACOLOGY

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

Albert Hsu, Daniel M. Togasaki, Erwan Bezard, Pierre Sokoloff, J. William Langston, Donato A. Di Monte and Maryka Quik
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 770-777; DOI: https://doi.org/10.1124/jpet.104.071142

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Research ArticleBEHAVIORAL PHARMACOLOGY

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

Albert Hsu, Daniel M. Togasaki, Erwan Bezard, Pierre Sokoloff, J. William Langston, Donato A. Di Monte and Maryka Quik
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 770-777; DOI: https://doi.org/10.1124/jpet.104.071142
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