Deepening the Topology
of the Translocator Protein Binding Site by Novel <i>N</i>,<i>N</i>‑Dialkyl-2-arylindol-3-ylglyoxylamides
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Abstract
As a continuation of our studies
on 2-phenylindol-3-ylglyoxylamides as potent and selective translocator
protein (TSPO) ligands, two subsets of novel derivatives, featuring
hydrophilic group (OH, NH<sub>2</sub>, COOH) at the para-position
of the pendent 2-phenyl ring (<b>8</b>–<b>16</b>) or different 2-aryl moieties, namely, 3-thienyl, <i>p</i>-biphenyl, 2-naphthyl (<b>23</b>–<b>35</b>), were
synthesized and biologically evaluated, some of them showing <i>K</i><sub>i</sub> values in the subnanomolar range and the 2-naphthyl
group performance being the best. The resulting SARs confirmed the
key role played by interactions taking place between ligands and the
lipophilic L1 pocket of the TSPO binding site. Docking simulations
were performed on the most potent compound of the present series (<b>29</b>) exploiting the recently available 3D structures of TSPO
bound to its standard ligand (PK11195). Our theoretical model was
fully consistent with SARs of the newly investigated as well of the
previously reported 2-phenylindol-3-ylglyoxylamide derivatives