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

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.

Modeling Parkinson's Disease in Primates: The MPTP Model

“…However, the most debilitating class of motor fluctuation is involuntary movements known as L-dopa-induced dyskinesia (LID). Four species have been regularly used, namely the macaque monkeys (macaca mulatta and macaca fascicularis) Berton et al 2009;Ahmed et al 2010;Fasano et al 2010;Rylander et al 2010), the marmoset (callithrix jacchus) (Pearce et al 1998;Henry et al 2001Henry et al , 2003Smith et al 2002;Savola et al 2003;Hill et al 2004a,b) and the squirrel (Saimiri sciureus) monkeys Hsu et al 2004), although the most human-like ones are displayed by the macaques (Bezard et al 2001a;Jenner 2008). Those macaques with LID show various combinations of choreic-athetoid (i.e., characterized by constant writhing and jerking motions), dystonic and even ballistic movements (i.e., large-amplitude flinging, flailing movements), although less frequently for those latter Gold et al 2007;Berton et al 2009;Ahmed et al 2010;Fasano et al 2010;Rylander et al 2010).…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…In another study, performed in the MPTP-lesioned macaque, antagonizing D 3 receptors with nafadotride led to a reduction of previously established LID, although this was associated with a reduction in L-DOPA antiparkinsonian action (Bezard et al, 2003), whereas treatment with the D 3 partial agonist BP897 reduced dyskinesia severity without adversely affecting parkinsonism (Bezard et al, 2003). In contrast, in the MPTP-lesioned squirrel monkey, BP897 only exerted a mild antidyskinetic effect and impaired L-DOPA antiparkinsonian action (Hsu et al, 2004). Part of the discrepancy between these studies may result from the pharmacology of the agents used, because there has been some discussion as to the selectivity of nafadotride (Bezard et al, 2003) and BP897 (Pilla et al, 1999), whereas part may result from the models used.…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…Recent studies have implicated the D3 receptor in the induction of dyskinesia, 305 and the partial D3 agonist BP897 ([N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide) has been shown to provide antiparkinsonian effects and reversal of dyskinesia in both macaque and squirrel monkeys. 1034 These types of agents warrant further investigation in patients with PD. The dopamine agonist SLV308 (Pardoprunox) is a partial agonist at dopamine D2 and D3 receptors and a full agonist at the serotonin 5-HT(1A) receptor.…”