Integrated Synthetic, Pharmacological, and Computational Investigation of cis-2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4

Christo Christov, Patricia González-Bulnes, Fanny Malhaire, Tatyana Karabencheva, Cyril Goudet, Jean Philippe Pin, Amadeu Llebaria, Jesús Giraldo

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10 Citations (Scopus)

Abstract

2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol. 2008, 74, 1345-1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High-level quantum chemical calculations were carried out to characterize the structures of minimum energy in all-isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R,2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R,2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.A helping handedness: Pharmacological assays revealed that the 1R,2S enantiomer of cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid possesses significantly higher potency than its molecular mirror image, thereby emphasizing the role that ligand chirality may have in mGluR4 allosteric modulation. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Original languageEnglish
Pages (from-to)131-140
JournalChemMedChem
Volume6
Issue number1
DOIs
Publication statusPublished - 3 Jan 2011

Keywords

  • Allosteric modulators
  • Computational chemistry
  • Enantioselectivity
  • G-protein-coupled receptors
  • MGluR4

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