Evaluation of D2 and D3 dopamine receptor selective compounds on L-dopa-dependent abnormal involuntary movements in rats.
Evaluation of D2 and D3 dopamine receptor selective compounds on L-dopa-dependent abnormal involuntary movements in rats.
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DOI：
10.1016/j.neuropharm.2009.01.019
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发表时间：
2009-05
影响因子：
4.7
通讯作者：
Luedtke RR
中科院分区：
文献类型：
--
作者：
Kumar R;Riddle LR;Griffin SA;Chu W;Vangveravong S;Neisewander J;Mach RH;Luedtke RR
研究了一组新型D2和D3多巴胺受体选择性拮抗剂、部分激动剂和完全激动剂对6-羟基多巴胺(6-OHDA)单侧损毁雄性SD大鼠L-多巴相关的异常不自主运动(AIMS)的抑制作用。帕金森病患者长期服用L多巴后，常可观察到LID。用转染人D2Long或D3多巴胺受体亚型的HEK 293细胞，用Forsklin依赖的腺苷环化酶抑制试验测定这些多巴胺能化合物的内在活性。在最初的实验中，5-HT1A受体选择性部分激动剂丁螺环酮被用来验证我们量化总AIMS和AIMS减去运动得分的能力。两种D2多巴胺受体选择性拮抗剂SV156和SV293被评估并发现最小程度地降低了这些动物的AIM评分。我们的D3多巴胺受体选择性化合物WC系列中的四个成员WC10、WC21、WC26和WC44在D3多巴胺受体亚型上具有不同的内在活性，也被评估并发现以剂量依赖的方式降低AIM评分。与L多巴/苯丝肼提前60分钟给药相比，与L-多巴同时给药时，这些化合物的体内疗效增加。D3受体拮抗剂WC10对达到最大强度的非自主运动也有抑制作用。与D1样多巴胺受体选择性激动剂SKF 81297和D2样多巴胺受体激动剂溴隐亭不同，D3型受体选择性激动剂WC 44给药后没有观察到异常不自主运动。此外，我们使用旋转臂装置评估了这四种D3多巴胺受体选择性化合物对a)自发运动和b)协调性和敏捷性的影响。我们还使用圆柱体测试来评估L-多巴在存在或不存在测试化合物的情况下对大鼠每条前肢的自发和独立使用的影响。这些研究结果表明，取代苯基哌嗪D3多巴胺受体选择性化合物是治疗帕金森病患者L多巴相关性运动障碍的潜在药物。
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.
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影响因子：
3.6
作者：
Gay, EA;Urban, JD;Mailman, RB
通讯作者：
Mailman, RB
影响因子：
4.1
作者：
Guigoni, C;Aubert, I;Bezard, E
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Bezard, E
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82.9
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Bézard, E;Ferry, S;Sokoloff, P
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影响因子：
9.9
作者：
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Chase, TN
影响因子：
4.7
作者：
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通讯作者：
Cenci, MA