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首页> 美国卫生研究院文献>other >Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure−Activity Relationship Study of N6‑(2-(4-(1H‑Indol-5-yl)piperazin-1-yl)ethyl)‑N6‑propyl-4567-tetrahydrobenzodthiazole-26-diamine Analogues: Implication in the Treatment of Parkinson’s Disease
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Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure−Activity Relationship Study of N6‑(2-(4-(1H‑Indol-5-yl)piperazin-1-yl)ethyl)‑N6‑propyl-4567-tetrahydrobenzodthiazole-26-diamine Analogues: Implication in the Treatment of Parkinson’s Disease

机译：N6-（2-（4-（1（4-（1H-Indol-5-yl）piperazin-1-yl）ethyl）-N6-丙基-）的结构-活性关系研究开发出高强度的D2 / D3激动剂和部分激动剂4567-四氢苯并d噻唑-26-二胺类似物：对帕金森氏病的治疗意义

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Our structure−activity relationship studies with N6-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives led to development of a lead compound (−)->21a which exhibited very high affnity (Ki, D2 = 16.4 nM, D3 = 1.15 nM) and full agonist activity (EC50 (GTPγS); D2 = 3.23 and D3 = 1.41 nM) at both D2 and D3 receptors. A partial agonist molecule (−)->34 (EC50 (GTPγS); D2 = 21.6 (Emax = 27%) and D3 = 10.9 nM) was also identified. In a Parkinson’s disease (PD) animal model, (−)->21a was highly effcacious in reversing hypolocomotion in reserpinized rats with a long duration of action, indicating its potential as an anti-PD drug. Compound (−)>-34 was also able to elevate locomotor activity in the above PD animal model significantly, implying its potential application in PD therapy. Furthermore, (−)>-21a was shown to be neuroprotective in protecting neuronal PC12 from toxicity of 6-OHDA. This report, therefore, underpins the notion that a multifunctional drug like (−)>-21a might have the potential not only to ameliorate motor dysfunction in PD patients but also to modify disease progression by protecting DA neurons from progressive degeneration.
机译：我们与N 6 -（2-（4-（1H-吲哚-5-基）哌嗪-1-基）乙基）-N 6 的构效关系研究-丙基-4,5,6,7-四氢苯并[d]噻唑-2,6-二胺衍生物导致形成铅化合物（-）-> 21a ，该化合物表现出很高的亲和力（Ki， D2和D3受体的D2 = 16.4 nM，D3 = 1.15 nM）和完全激动剂活性（EC50（GTPγS）； D2 = 3.23和D3 = 1.41 nM）。还鉴定出部分激动剂分子（-）-> 34 （EC50（GTPγS）； D2 = 21.6（Emax = 27％）和D3 = 10.9 nM）。在帕金森氏病（PD）动物模型中，（-）-> 21a 在逆转再固定化的大鼠中具有很长的作用持续时间，对逆转运动非常有效，表明其作为抗P​​D药物的潜力。化合物（-）> -34 还能够显着提高上述PD动物模型的运动能力，这暗示其在PD治疗中的潜在应用。此外，（-）> -21a 被证明在保护神经元PC12免受6-OHDA毒性方面具有神经保护作用。因此，该报告巩固了这样的观念，即多功能药物如（-）> -21a 可能不仅具有改善PD患者运动功能障碍的潜力，而且还可以通过保护DA神经元免于进展而改变疾病进展退化。

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