The substituted 4-phenylpiperazine D3 dopamine receptor selective antagonist PG01037 ((E)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)- 4-(pyridin-2-yl)benzamide) was reported to attenuate l-dopa-associated abnormal involuntary movements (AIMs) in unilaterally lesioned rats, a model of l-dopa-dependent dyskinesia in patients with Parkinson's Disease (Kumar et al., 2009a). We now report that PG01042 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl) butyl)-4-(pyridin-3-yl)benzamide), which is a D3 dopamine receptor selective agonist for adenylyl cyclase inhibition and a partial agonist for mitogenesis, is also capable of attenuating AIMs scores. The intrinsic activity of PG01037 and PG01042 were determined using a) a forskolin-dependent adenylyl cyclase inhibition assay and b) an assay for agonist-associated mitogenesis. It was observed that the in vivo efficacy of PG01042 increased when administered by intraperitoneal (i.p.) injection simultaneously with l-dopa/benserazide (8 mg/kg each), as compared to a 60 min or 30 min pretreatment. PG01042 was found to attenuate AIM scores in these animals in a dose dependent manner. While PG01042 did not effectively inhibit SKF 81297-dependent AIMs, it inhibited apomorphine-dependent AIM scores. Rotarod studies indicate that PG01042 at a dose of 10 mg/kg did not adversely affect motor coordination of the unilaterally lesioned rats. Evaluation of lesioned rats using a cylinder test behavioral paradigm indicated that PG01042 did not dramatically attenuate the beneficial effects of l-dopa. These studies and previously published studies suggest that both D3 dopamine receptor selective antagonists, partial agonists and agonists, as defined by an adenylyl cyclase inhibition assay and a mitogenic assay, are pharmacotherapeutic candidates for the treatment of l-dopa-associated dyskinesia in patients with Parkinson's Disease.
Bibliographical noteFunding Information:
This research was supported by a Community Fast Track 2006 from the Michael J. Fox Foundation for Parkinson’s Research and R-01 DA13584-03S1 (RRL) and the NIDA-IRP (AHN and PG). The authors would like to thank Drs. Eunson Jung and Nathalie Sumien for their assistance with the statistical analysis and helpful discussions. The authors also thank the NIDA Addiction Treatment Discovery Program for contract resources used to conduct the D2 and D3 receptor based mitogenic assays. These were contract N01DA-1-8816 to SRI International (PI Larry Toll) and interagency agreement IAGY1 DA 5007-05 to the Portland VA Medical Center (PI Aaron Janowsky).
- D3 dopamine receptors
- Dopamine receptors
- Parkinson's Disease