Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis

Journal of Medicinal Chemistry
Federico Da SettimoClaudia Martini

Abstract

Novel N,N-disubstituted indol-3-ylglyoxylamides (1-56), bearing different combinations of substituents R 1-R 5, were synthesized and evaluated as ligands of the translocator protein (TSPO), the 18 kDa protein representing the minimal functional unit of the "peripheral-type benzodiazepine receptor" (PBR). Most of the new compounds showed a nanomolar/subnanomolar affinity for TSPO and stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classic TSPO ligands such as PK 11195. Moreover, when evaluated in vivo by means of the elevated-plus-maze (EPM) paradigm in the rat, compound 32, the best-performing derivative in terms of TSPO affinity and pregnenolone production, showed clear anxiolytic effects. The results of this study suggested that the novel N,N-disubstituted indol-3-ylglyoxylamides may represent a promising class of compounds potentially suited for the treatment of anxiety disorders.

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Citations

Dec 2, 2010·Nature Reviews. Drug Discovery·Rainer RupprechtMichael Schumacher
Dec 17, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Kazuhiro TokudaCharles F Zorumski
May 6, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Andrew S MidzakVassilios Papadopoulos
Jul 16, 2015·Journal of Medicinal Chemistry·Elisabetta BarresiClaudia Martini
Apr 21, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Anna SantoroRosaria Meli
Jul 17, 2016·The Journal of Endocrinology·Vimal Selvaraj, Lan N Tu
Jan 12, 2016·Scientific Reports·Barbara CostaClaudia Martini
Jun 5, 2012·Pharmacological Reports : PR·Anders I Svensson
Jul 2, 2016·International Journal of Molecular Sciences·Eleonora Da PozzoClaudia Martini
Nov 1, 2015·Doklady. Biochemistry and Biophysics·T A GudashevaS B Seredenin
Sep 20, 2019·Journal of Neuroendocrinology·Amandine GrimmAnne Eckert
May 21, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sabrina TalianiGiovanni Greco
Apr 16, 2019·Chemistry : a European Journal·Felipe L CoelhoPaulo H Schneider
Nov 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tatiana A GudashevaSergei B Seredenin
Oct 22, 2020·European Journal of Medicinal Chemistry·Elisabetta BarresiSabrina Taliani
Jan 13, 2009·Journal of Medicinal Chemistry·Alana M ScarfMichael Kassiou
Aug 10, 2011·European Journal of Medicinal Chemistry·Barbara CosimelliClaudia Martini

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