Evaluation of the D3 dopamine receptor selective antagonist PG01037 on l-dopa-dependent abnormal involuntary movements in rats

Abstract

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 minutes after L-dopa/benserazide administration, as compared to a 60 minute, 30 minute or 0 minute 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 IC50 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.

Evaluation of the D3 dopamine receptor selective agonist/partial agonist PG01042 on l-dopa dependent animal involuntary movements in rats

“…AIMs ratings were performed by an investigator who was unaware of the pharmacological intervention, as previously described (Kumar et al, 2009a). After injection of the L-dopa, the severity of the AIMs was quantified using lesioned rats that were observed individually in their home cages at 20 minute intervals, starting 10 minutes after the injection of L-dopa, until the AIMs subsided (approximately 2 hours).…”

“… 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.…”

Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression

“…Thus, the up-regulation of dopamine D3 receptors may represent a parallel pathological mechanism, which further exacerbates D1R sensitization, contributing to the development of LID. In line with this possibility, several antagonists at dopamine D3 receptors have been shown to reduce the dyskinetic response to l -DOPA (Bezard et al 2003; Kumar et al 2009; Visanji et al 2009; but see also Mela et al 2010). …”

Dopamine D1 and D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration

“…PG01037 was initially described (Grundt et al, 2005; 2007) as a highly potent (Ki=0.7 nM) D3 receptor-selective antagonist (133-fold over D2 receptors). Although PD01037 also showed actions with low affinities at histamine H1, 5-HT1A, 2A, 2C, α1 and α2 adrenergic receptors (Kumar et al, 2009), it preferentially binds to D3 receptors. PG01037 rapidly penetrates the blood brain barrier and selectively localizes in D3 receptor-rich regions, such as the nucleus accumbens (NAc), Islets of Calleja and the hippocampus (Grunt et al, 2007).…”