p.) injection 15 min after L-dopa/benserazide ad ministration,
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 PGO1037 at Cyclopamine solubility dmso a dose of 10 mg/kg did not adversely affect motor ARS-1620 chemical structure 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. (C) 2009 Published by Elsevier Ltd.”
“A panel of novel D2 and D3 dopamine receptor selective antagonists, partial agonists and full agonists have been evaluated for the ability to attenuate L-dopa-associated abnormal involuntary
movements (AIMs) in 6-hydroxydopamine (6-OHDA) unilaterally lesioned male Sprague Dawley rats, which is an animal model Of L-dopa-induced dyskinesia (LID). LID is often observed in patients with Parkinson’s Disease following chronic treatment with L-dopa. The intrinsic activity of these dopaminergic compounds was determined using a forskolin-dependent
adenylyl cyclase inhibition CA3 chemical structure assay with transfected HEK 293 cells expressing either the human D2Long or D3 dopamine receptor subtype. For the initial experiments the 5-HT1A receptor selective partial agonist buspirone was used to verify our ability to quantitate changes in total AIMs and AIMs minus locomotor scores. Two D2 dopamine receptor selective antagonists, SV 156 and SV 293, were evaluated and found to minimally attenuate AIM scores in these animals. Four members of our WC series of D3 dopamine receptor selective compounds of varying intrinsic activity at the D3 dopamine receptor subtype, WC 10, WC 21, WC 26 and WC 44, were also evaluated and found to attenuate AIM scores in a dose dependent manner. The in vivo efficacy of the compounds increased when they were administered simultaneously With L-dopa, as compared to when the compounds were administered 60 min prior to the L-dopa/benserazide. It was also found that the D3 receptor antagonist WC 10 could inhibit the involuntary movements after they had achieved maximum intensity.