Structure-Based Design of PDZ Ligands as Inhibitors of 5-HT2A Receptor/PSD-95 PDZ1 Domain Interaction Possessing Anti-hyperalgesic Activity

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• 作者：Alexandre Vogrig ; Liam Dorr ; Naoual Bouzidi ; Benjamin Boucherle ; Anne-Sophie Wattiez ; Elisabeth Cassier ; Gary Vallon ; Isabelle Ripoche ; Isabelle Abrunhosa-Thomas ; Philippe Marin ; Lionel Nauton ; Vincent Thery ; Christine Courteix ; Lu-Yun Lian ; Sylvie Ducki
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：October 18, 2013
• 年：2013
• 卷：8
• 期：10
• 页码：2209-2216
• 全文大小：574K
• 年卷期：v.8,no.10(October 18, 2013)
• ISSN：1554-8937

文摘

Disrupting the interaction between the PDZ protein PSD-95 and the C-terminal domain of the 5-HT_2A 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 ¹H鈥?sup>15N heteronuclear single-quantum coherence (HSQC) experiments and two of them were able to inhibit the interaction between PSD-95 and the 5-HT_2A 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-HT_2A receptor antagonist M100907, consistent with an inhibitory effect upon 5-HT_2A 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.