Exploring the Active Conformation of Cyclohexane Carboxylate Positive Allosteric Modulators of the Type 4 Metabotropic Glutamate Receptor

• DOI: 10.1002/cmdc.201402190
• Publication Date: 2014-09-05T11:31:35Z
• Authors: Xavier Rovira; Youssef Harrak; Ana Trapero; Patricia González...; Fanny Malhaire; Jean‐Philippe Pin; Cyril Goudet; Jesús Giraldo; Amadeu Llebaria
• Keywords: 0301 basic medicine; conformational probes; Cyclohexanecarboxylic Acids; metabotropic glutamate receptors; Molecular Conformation; Receptors, Metabotropic Glutamate; GPCRs; Structure-Activity Relationship; 03 medical and health sciences; Allosteric Regulation; Receptors; Metabotropic Glutamate/*chemistry/metabolism; Humans; Anilides; norbornanes; 0303 health sciences; Cyclohexanecarboxylic Acids/chemical synthesis/*chemistry/metabolism; Stereoisomerism; Anilides/*chemistry/metabolism; Norbornanes; 3. Good health; Norbornanes/chemistry; [SDV] Life Sciences [q-bio]; HEK293 Cells; Drug Design; allosteric modulators; Protein Binding

AbstractThe 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.