Clermont Université, Université Blaise Pascal , Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
ACS Chem Biol. 2013 Oct 18;8(10):2209-16. doi: 10.1021/cb400308u. Epub 2013 Aug 23.
Disrupting the interaction between the PDZ protein PSD-95 and the C-terminal domain of the 5-HT2A serotonin receptor has been shown to reduce hyperalgesia in a rodent model of neuropathic pain. Here, we designed and synthesized PDZ ligands capable of binding to the first PDZ domain (PDZ1) of the PSD-95 protein and evaluated their biological activity in vitro and in vivo. A series of substituted indoles was identified by docking simulations, and six novel analogues were synthesized. Three analogues displayed strong interactions with the first PDZ domain (PDZ1) of PDZ-95 in (1)H-(15)N heteronuclear single-quantum coherence (HSQC) experiments and two of them were able to inhibit the interaction between PSD-95 and the 5-HT2A receptor in vitro. We identified compound 8b as the analogue able to significantly suppress mechanical hyperalgesia in an experimental model of traumatic neuropathic pain in the rat. This effect was suppressed by the coadministration of the 5-HT2A receptor antagonist M100907, consistent with an inhibitory effect upon 5-HT2A receptor/PSD-95 interaction. Finally, we determined an NMR-restraint driven model structure for the PSD95 PDZ1/8b complex, which confirms that indole 8b binds to the putative PDZ-ligand binding site.
阻断 PDZ 蛋白 PSD-95 与 5-HT2A 血清素受体 C 端结构域的相互作用，已被证明可减轻神经病理性疼痛啮齿动物模型中的痛觉过敏。在这里，我们设计并合成了能够与 PSD-95 蛋白的第一个 PDZ 结构域（PDZ1）结合的 PDZ 配体，并在体外和体内评估了它们的生物学活性。通过对接模拟确定了一系列取代的吲哚，并合成了六个新的类似物。三个类似物在（1）H-（15）N 异核单量子相干（HSQC）实验中与 PDZ-95 的第一个 PDZ 结构域（PDZ1）显示出强烈的相互作用，其中两个能够抑制 PSD-95 和 5-HT2A 受体之间的相互作用在体外。我们确定化合物 8b 是能够显著抑制创伤性神经病理性疼痛大鼠实验模型中机械性痛觉过敏的类似物。这种作用被 5-HT2A 受体拮抗剂 M100907 的共同给药所抑制，这与对 5-HT2A 受体/PSD-95 相互作用的抑制作用一致。最后，我们确定了 PSD95 PDZ1/8b 复合物的 NMR 约束驱动模型结构，该结构证实了吲哚 8b 结合到假定的 PDZ-配体结合位点。
