Evaluation of the D3 dopamine receptor selective agonist/partial agonist PG01042 on L-dopa dependent animal involuntary movements in rats.
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.
Riddle
Lindsay R
LR
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie, Fort Worth, TX 76107, USA.
Kumar
Rakesh
R
Griffin
Suzy A
SA
Grundt
Peter
P
Newman
Amy Hauck
AH
Luedtke
Robert R
RR
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D054333:Drug Partial Agonism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D020820:Dyskinesias / Q000188:drug therapy / Q000378:metabolism; D007980:Levodopa / Q000502:physiology*; D008297:Male; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism
D001549:Benzamides; D018491:Dopamine Agonists; C562350:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-3-yl)benzamide; D010879:Piperazines; D050637:Receptors, Dopamine D3; D007980:Levodopa