Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 1522 82

The role of D(3) receptors in the antiparkinsonian actions of l-DOPA and l-DOPA-induced dyskinesia (LID) remains unclear. The D(3) receptor partial agonist BP897 attenuates LID in primates without affecting the antiparkinsonian actions of l-DOPA, suggesting that "normalization" of D(3) activity is antidyskinetic [Bezard, E., Ferry, S., Mach, U., Stark, H., Leriche, L., Boraud, T., Gross, C., and Sokoloff, P., 2003. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D(3) receptor function. Nat. Med. 9, 762-767]. However, subsequent studies have questioned these findings [Hsu, A., Togasaki, D.M., Bezard, E., Sokoloff, P., Langston, J.W., Di Monte, D.A., and Quik, M., 2004. Effect of the D(3) 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. J. Pharmacol. Exp. Ther. 311, 770-777]. The D(3) receptor antagonist S33084 is not antidyskinetic yet enhances the antiparkinsonian actions of l-DOPA, suggesting that stimulation of D(3) receptors is not involved in LID. Here, we address the possibility that in vivo BP897 acts via mechanisms in addition to attenuation of D(3) signaling. l-DOPA (125 mg/kg) elicits hyperkinesia in reserpine-treated rats, the vertical component of which (rearing) is attenuated by agents with antidyskinetic actions in MPTP-lesioned primates and Parkinson's disease (PD) [Johnston, T.H., Lee, J., Gomez-Ramirez, J., Fox, S.H., and Brotchie, J.M., 2005. A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease. Exp. Neurol. 191, 243-250]. BP897 (0.1, 0.3, 1.0 and 3 mg/kg) reduced l-DOPA-induced rearing by 0%, 44%, 86% and 57% respectively. In contrast, S33084 had no effect on l-DOPA-induced rearing (0.1 mg/kg, 115%; 0.3 mg/kg, 94%, 1 mg/kg, 134%; 3 mg/kg, 100%, of vehicle, all P > 0.05). Furthermore, S33084 failed to antagonize the effects of BP897 on l-DOPA-induced rearing. The influence of BP897 on l-DOPA-induced rearing was, however, mimicked by the selective D(2) antagonist L741,626. Finally, BP897 attenuated l-DOPA-induced horizontal activity, an action attenuated by S33084 and mimicked by L741,626. Thus, while BP897 may reduce LID, we raise the possibility that receptors other than D(3) receptors might be involved in this action.
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PMID:Actions at sites other than D(3) receptors mediate the effects of BP897 on l-DOPA-induced hyperactivity in monoamine-depleted rats. 1681 82