Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu<inf>5</inf>negative allosteric modulation

Xavier Gómez-Santacana, James A.R. Dalton, Xavier Rovira, Jean Philippe Pin, Cyril Goudet, Pau Gorostiza, Jesús Giraldo, Amadeu Llebaria

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

© 2017 Elsevier Masson SAS Modulation of metabotropic glutamate receptor 5 (mGlu5) with partial allosteric antagonists has received increased interest due to their favourable in vivo activity profiles compared to the unfavourable side-effects of full inverse agonists. Here we report on a series of bispyridine benzene derivatives with a functional molecular switch affecting antagonistic efficacy, shifting from inverse agonism to partial antagonism with only a single change in the substitution pattern of the benzene ring. These efficacy changes are explained through computational docking, revealing two different receptor conformations of different energetic stability and different positional isomer binding preferences.
Original languageEnglish
Pages (from-to)567-576
JournalEuropean Journal of Medicinal Chemistry
Volume127
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Antagonist
  • Inverse agonist
  • Isomers
  • mGlu 5
  • NAM
  • Partial efficacy

Fingerprint Dive into the research topics of 'Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu<inf>5</inf>negative allosteric modulation'. Together they form a unique fingerprint.

Cite this