title: Structure-based design of PDZ ligands as inhibitors of 5-HT(2A) receptor/PSD-95 PDZ1 domain interaction possessing anti-hyperalgesic activity.
abstract: 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.
authors.affiliation: Clermont Université, Université Blaise Pascal , Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vogrig
authors.forename: Liam
authors.initials: L
authors.lastname: Dorr
authors.forename: Naoual
authors.initials: N
authors.lastname: Bouzidi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boucherle
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Wattiez
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Cassier
authors.forename: Gary
authors.initials: G
authors.lastname: Vallon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ripoche
authors.forename: Isabelle
authors.initials: I
authors.lastname: Abrunhosa-Thomas
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Lionel
authors.initials: L
authors.lastname: Nauton
authors.forename: Vincent
authors.initials: V
authors.lastname: Thery
authors.forename: Christine
authors.initials: C
authors.lastname: Courteix
authors.forename: Lu-Yun
authors.initials: LY
authors.lastname: Lian
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ducki
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D003198:Computer Simulation; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D054731:PDZ Domains; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists