Exploring the active conformation of cyclohexane carboxylate positive allosteric modulators of the type 4 metabotropic glutamate receptor

Xavier Rovira, Youssef Harrak, Ana Trapero, Patricia González-Bulnes, Fanny Malhaire, Jean Philippe Pin, Cyril Goudet, Jesffls Giraldo, Amadeu Llebaria

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. The active conformation of a family of metabotropic glutamate receptor subtype 4 (mGlu<inf>4</inf>) positive allosteric modulators (PAMs) with the cyclohexane 1,2-dicarboxylic scaffold present in cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041) was investigated by testing structurally similar six-membered ring compounds that have a locked conformation. The norbornane and cyclohexane molecules designed as mGlu<inf>4</inf> conformational probes and the enantiomers of the trans diastereomer were computationally characterized and tested in mGlu<inf>4</inf> pharmacological assays. The results support a VU0155041 active conformation, with the chair cyclohexane having the aromatic amide substituent in an axial position and the carboxylate in an equatorial position. Moreover, the receptor displays enantiomeric discrimination of the chiral PAMs. The constructed pharmacophore characterized a highly constrained mGlu<inf>4</inf> allosteric binding site, thus providing a step forward in structure-based drug design for mGlu<inf>4</inf> PAMs.
Original languageEnglish
Pages (from-to)2685-2698
JournalChemMedChem
Volume9
Issue number12
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Allosteric modulators
  • Conformational probes
  • GPCRs
  • Metabotropic glutamate receptors
  • Norbornanes

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