Evaluation of D2 and D3 dopamine receptor selective compounds on l-dopa-dependent abnormal involuntary movements in rats

Abstract

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 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, SV156 and SV293, 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 minutes 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. Unlike the D1-like dopamine receptor selective agonist SKF 81297 and the D2-like dopamine receptor agonist bromocriptine which can precipitate abnormal involuntary movements in these unilaterally lesioned animals, abnormal involuntary movements were not observed after administration of our D3 receptor selective agonist WC 44. In addition, we evaluated the effect of these four D3 dopamine receptor selective compounds for their effect on a) spontaneous locomotion and b) coordination and agility using a rotarod apparatus. We also used a cylinder test to assess the effect of L-dopa on spontaneous and independent use of each of the rat’s forelimbs in the presence or absence of test compound. The results of these studies suggest that substituted phenylpiperazine D3 dopamine receptor selective compounds are potential pharmacotherapeutic agents for the treatment of L-dopa-associated dyskinesia in patients with Parkinson’s Disease.

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

“…22,31 Development of D2 and D3 receptor subtype selective compounds would provide the pharmacological tools to enable the neuroscience community to better understand the role of these two receptor subtypes in complex behavioral and physiological processes. Furthermore, D2-like receptor subtype selective compounds of varying intrinsic activity have the potential for development of (a) pharmacotherapeutic agents for the treatment of neurological disorders, 6 neuropsychiatric disease, 32 and psychostimulant abuse, 33 and (b) neuroimaging agents to study the differential expression and regulation of D2-like dopamine receptors. 34,35 We initially assumed that ligand binding selectivity would be achieved by developing compounds capable of exploiting differences in contact residues between these two structurally related receptor subtypes.…”

The Effect of SV 293, a D2 Dopamine Receptor-Selective Antagonist, on D2 Receptor-Mediated GIRK Channel Activation and Adenylyl Cyclase Inhibition

“…For example, we have used SV 293 to investigate the utility of using D2-like receptor-selective antagonists for attenuating L -dopa-dependent abnormal involuntary movements in unilaterally lesioned animals, which is a rodent model of L -dopa-induced dyskinesia, a common side effect associated with the chronic administration of L -dopa in individuals with Parkinson's disease [5]. In those studies we reported that while D3 receptor-selective compounds attenuated abnormal involuntary movement scores, SV 293, at a dose of 10 mg/kg, exhibited only marginal activity.…”

“…These neuronal systems are involved in movement coordination, cognition, emotion, affect, memory and the regulation of prolactin secretion by the pituitary. Alterations in the dopaminergic pathways are thought to be involved in the pathogenesis of neurological, neuropsychiatric and hormonal disorders, including Parkinson's disease, schizophrenia and hyperprolactinemia [1,2,3,4,5,6]. In addition, modulation of the dopaminergic pathways is thought to occur as a consequence of acute and chronic abuse of pyschostimulants, including cocaine and amphetamines [7,8].…”

Reduction of Cocaine Self-Administration and D3 Receptor-Mediated Behavior by Two Novel Dopamine D3 Receptor-Selective Partial Agonists, OS-3-106 and WW-III-55

“…We previously reported on the development of a series of arylamide phenylpiperazines that have high affinity for D3Rs, moderate D3R:D2R binding selectivity (i.e., 23-51-fold), and low log P values (2.9-3.5) (Chu et al, 2005;Kumar et al, 2009). We found that three of these compounds-WC10, WC26, and WC44-reduced cocaine self-administration (Cheung et al, 2012).…”

“…Systemic cocaine, OS-3-106, WW-III-55, and their vehicles were given intraperitoneally, and 7-OH-DPAT and its vehicle were given subcutaneously. OS-3-106 and WW-III-55 were injected 5 minutes before the start of the test session, based on our previous study showing that arylamide phenylpiperazines attenuated L-DOPAinduced dyskinesia (Kumar et al, 2009) and reduced locomotor activity (Cheung et al, 2012) within this time frame.…”