Structure-based design of PDZ ligands as inhibitors of 5-HT(2A) receptor/PSD-95 PDZ1 domain interaction possessing anti-hyperalgesic activity

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...

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Published in:ACS chemical biology 2013-10, Vol.8 (10), p.2209-2216
Main Authors: Vogrig, Alexandre, Dorr, Liam, Bouzidi, Naoual, Boucherle, Benjamin, Wattiez, Anne-Sophie, Cassier, Elisabeth, Vallon, Gary, Ripoche, Isabelle, Abrunhosa-Thomas, Isabelle, Marin, Philippe, Nauton, Lionel, Thery, Vincent, Courteix, Christine, Lian, Lu-Yun, Ducki, Sylvie
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacology
Animals
Computer Simulation
Disease Models, Animal
Hyperalgesia - drug therapy
Ligands
Magnetic Resonance Spectroscopy
Molecular Structure
PDZ Domains
Rats
Receptor, Serotonin, 5-HT2A - metabolism
Serotonin 5-HT2 Receptor Antagonists - chemical synthesis
Serotonin 5-HT2 Receptor Antagonists - chemistry
Serotonin 5-HT2 Receptor Antagonists - pharmacology
Structure-Activity Relationship
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Summary: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.
ISSN:1554-8937
DOI:10.1021/cb400308u