Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABAA Receptor.

ACS Medicinal Chemistry Letters
Annet E M BlomDennis A Dougherty

Abstract

γ-Aminobutyric acid type A (GABAA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain a challenge. Selective targeting of GABAA receptors could mitigate this problem. Here, we describe the synthesis and functional evaluation of a novel series of pyrroloindolines that display significant modulation of the GABAA receptor, acting as PAMs. We found that halogen incorporation at the C5 position greatly increased the PAM potency relative to the parent ligand, while substitutions at other positions generally decreased potency. Mutagenesis studies suggest that the binding site lies at the top of the transmembrane domain.

References

May 10, 1994·Proceedings of the National Academy of Sciences of the United States of America·P B WingroveP J Whiting
Jan 5, 2001·Journal of Medicinal Chemistry·M L BolognesiC Melchiorre
Jul 23, 2003·Current Drug Targets. CNS and Neurological Disorders·John R Atack
Mar 2, 2005·Nature Reviews. Neuroscience·Mark Farrant, Zoltan Nusser
Sep 13, 2005·Bioorganic & Medicinal Chemistry Letters·Wesley P BlackabyJosé L Castro
Mar 28, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Susan M Hanson, Cynthia Czajkowski
Jun 5, 2008·Molecular Pharmacology·Julius MilitanteJoe Henry Steinbach
Jul 29, 2008·Journal of the American Chemical Society·Timothy Newhouse, Phil S Baran
Jan 6, 2009·Current Opinion in Psychiatry·Jean-Marc Cloos, Valérie Ferreira
Dec 17, 2009·Chemistry : a European Journal·Javier Ruiz-RodríguezRodolfo Lavilla
Jan 26, 2010·Trends in Pharmacological Sciences·Paul S Miller, Trevor G Smart
Sep 30, 2010·Journal of the American Chemical Society·Lindsay M RepkaSarah E Reisman
Jan 21, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Joachim RamerstorferMargot Ernst
May 5, 2011·Journal of the American Chemical Society·Filip KolundzicScott J Miller
Jan 11, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ayman K HamoudaJonathan B Cohen
Apr 2, 2013·Journal of the American Chemical Society·Madeleine E KiefferSarah E Reisman
Oct 29, 2013·Annual Review of Pharmacology and Toxicology·Uwe Rudolph, Hanns Möhler
Apr 30, 2014·Angewandte Chemie·Haoxuan Wang, Sarah E Reisman
Jan 21, 2015·Advances in Pharmacology·Werner Sieghart
Jun 21, 2016·Journal of Neurochemistry·Maria C MaldifassiErwin Sigel
Aug 20, 2016·Genes, Brain, and Behavior·D N StephensT Duka
Jul 20, 2017·Scientific Reports·Xenia SimeoneMargot Ernst
Oct 3, 2017·Nature Structural & Molecular Biology·Duncan LavertyTrevor G Smart
Nov 12, 2017·British Journal of Pharmacology·Marco TrevenMargot Ernst
Jun 29, 2018·Nature·Shaotong ZhuRyan E Hibbs
Jan 4, 2019·Nature·Simonas MasiulisA Radu Aricescu

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