Adenosine A2A antagonist:: A novel antiparkinsonian agent that does not provoke dyskinesia in Parkinsonian monkeys
Adenosine A2A antagonist:: A novel antiparkinsonian agent that does not provoke dyskinesia in Parkinsonian monkeys
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DOI：
10.1002/ana.410430415
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发表时间：
1998-04-01
影响因子：
11.2
通讯作者：
Jenner, P
中科院分区：
文献类型：
--
作者：
Kanda, T;Jackson, MJ;Jenner, P
用L-多巴疗法治疗帕金森病导致长期并发症，包括药物功效的丧失和运动障碍的发作。纹状体中的腺苷A（2A）受体选择性地定位于纹状体-苍白球通路的GABA能输出神经元，并且可以避免这些问题。新型腺苷A（2A）受体拮抗剂KW-6002在MPTP处理的灵长类动物中的抗帕金森病活性已被检测。口服KW-6002以剂量依赖性方式逆转MPTP治疗的普通绒猴的运动障碍。然而，KW-6002仅适度增加整体运动活动，并且不引起异常运动，例如刻板。KW-6002逆转运动障碍的能力在重复每日给药21天后得以维持，并且未观察到耐受性。KW-G 002在MPTP处理的灵长类动物中诱导很少或没有运动障碍，这些灵长类动物先前通过先前暴露于L-多巴而表现出运动障碍。这些结果表明，选择性腺苷A（2A）受体拮抗剂代表了一类新的抗帕金森病药物，改善残疾，不产生多动症，不诱导运动障碍。
Treatment of Parkinson's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia Adenosine A(2A) receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A(2A) receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-G002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A(2A) receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.