2 research outputs found
Access to 2,6-Disubstituted Piperidines: Control of the Diastereoselectivity, Scope, and Limitations. Applications to the Stereoselective Synthesis of (−)-Solenopsine A and Alkaloid (+)-241D
Scope
and limitations in the diastereoselective preparation of
2,6-<i>cis</i> or 2,6-<i>trans</i> disubstituted
piperidines are described, through intramolecular reaction of chiral
β′-carbamate-α,β-unsaturated ketone. This
methodology has been applied to the total synthesis of a few well
chosen examples, such as (−)-solenopsine A and alkaloid (+)-241D
Structure-Based Design of PDZ Ligands as Inhibitors of 5‑HT<sub>2A</sub> 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-HT<sub>2A</sub> 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 <i>in vitro</i> and <i>in
vivo</i>. 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 <sup>1</sup>H–<sup>15</sup>N heteronuclear single-quantum
coherence (HSQC) experiments and two of them were able to inhibit
the interaction between PSD-95 and the 5-HT<sub>2A</sub> receptor <i>in vitro</i>. We identified compound <b>8b</b> 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<sub>2A</sub> receptor antagonist M100907, consistent with an inhibitory effect
upon 5-HT<sub>2A</sub> receptor/PSD-95 interaction. Finally, we determined
an NMR-restraint driven model structure for the PSD95 PDZ1/<b>8b</b> complex, which confirms that indole <b>8b</b> binds to the
putative PDZ-ligand binding site