Evaluation of the D3 dopamine receptor selective antagonist PG01037 on L-dopa-dependent abnormal involuntary movements in rats.
The D3 dopamine receptor selective antagonist PG01037 has been evaluated for the ability to attenuate L-dopa-associated abnormal involuntary movements (AIMs) in unilaterally lesioned male Sprague-Dawley rats, which is a model of L-dopa-dependent dyskinesia in patients with Parkinson's Disease. The intrinsic activity of PG01037 was determined using a) a forskolin-dependent adenylyl cyclase inhibition assay with transfected HEK 293 cells expressing either the human D2Long or D3 dopamine receptor subtype and b) an assay for agonist-associated mitogenesis. For the initial experiments, the 5-HT1A receptor selective partial agonist buspirone was used as a positive control to verify our ability to quantitate changes in total AIMs and AIMs minus locomotor scores. Subcutaneous (s.c.) administration of PG01037 was found to have minimal effect on AIMs score. However, it was observed that the in vivo efficacy of PG01037 increased when administered by intraperitoneal (i.p.) injection 15 min after L-dopa/benserazide administration, as compared to a 60 min, 30 min or 0 min pretreatment. It was also found that i.p. administration of PG01037 could inhibit involuntary movements after they had achieved maximum intensity. PG01037 was found to attenuate AIM scores in these animals in a dose dependent manner with IC(50) value equal to a) 7.4 mg/kg following L-dopa/benserazide administration (8 mg/kg each, i.p.) and b) 18.4 mg/kg following the administration of apomorphine (0.05 mg/kg, s.c.). However, PG01037 did not effectively inhibit SKF 81297-dependent abnormal involuntary movements. Rotarod studies indicate that PG01037 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 PG01037 did not dramatically attenuate the beneficial effects of L-dopa. These studies suggest that D3 dopamine receptor selective antagonists are potential pharmacotherapeutic candidates for the treatment of L-dopa-associated dyskinesia in patients with Parkinson's Disease.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie, Fort Worth, TX 76107, USA.
Rakesh
R
Kumar
Lindsay
L
Riddle
Suzy A
SA
Griffin
Peter
P
Grundt
Amy Hauck
AH
Newman
Robert R
RR
Luedtke
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001552:Benzazepines / Q000494:pharmacology; D002460:Cell Line; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors*
D000067956:Adenylyl Cyclase Inhibitors; D000978:Antiparkinson Agents; D001549:Benzamides; D001552:Benzazepines; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; D011725:Pyridines; D050637:Receptors, Dopamine D3; D007980:Levodopa; C067113:SK&F 81297