Exploring the Active Conformation of Cyclohexane Carboxylate Positive Allosteric Modulators of the Type 4 Metabotropic Glutamate Receptor |
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| Authors: | Dr. Xavier Rovira Dr. Youssef Harrak Dr. Ana Trapero Dr. Patricia González‐Bulnes Fanny Malhaire Dr. Jean‐Philippe Pin Dr. Cyril Goudet Dr. Jesús Giraldo Dr. Amadeu Llebaria |
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| Affiliation: | 1. Laboratory of Molecular Neuropharmacology & Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra (Spain);2. Institut de Génomique Fonctionnelle, CNRS UMR5203, Université de Montpellier;3. U661, INSERM, 141 Rue de la Cardonille, 34094 Montpellier (France);4. Laboratory of Medicinal Chemistry, Department of Biomedicinal Chemistry, Institut de Química Avan?ada de Catalunya (IQAC‐CSIC), Jordi Girona 18‐26, 08034 Barcelona (Spain) |
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| Abstract: | ![]()
The active conformation of a family of metabotropic glutamate receptor subtype 4 (mGlu4) 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 mGlu4 conformational probes and the enantiomers of the trans diastereomer were computationally characterized and tested in mGlu4 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 mGlu4 allosteric binding site, thus providing a step forward in structure‐based drug design for mGlu4 PAMs. |
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| Keywords: | allosteric modulators conformational probes metabotropic glutamate receptors GPCRs norbornanes |
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