title: Exploring the active conformation of cyclohexane carboxylate positive allosteric modulators of the type 4 metabotropic glutamate receptor.
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.
authors.affiliation: Laboratory of Molecular Neuropharmacology & Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra (Spain); Institut de Génomique Fonctionnelle, CNRS UMR5203, Université de Montpellier; U661, INSERM, 141 Rue de la Cardonille, 34094 Montpellier (France).
authors.forename: Xavier
authors.initials: X
authors.lastname: Rovira
authors.forename: Youssef
authors.initials: Y
authors.lastname: Harrak
authors.forename: Ana
authors.initials: A
authors.lastname: Trapero
authors.forename: Patricia
authors.initials: P
authors.lastname: González-Bulnes
authors.forename: Fanny
authors.initials: F
authors.lastname: Malhaire
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
authors.forename: Jesús
authors.initials: J
authors.lastname: Giraldo
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
mesh_terms: D000494:Allosteric Regulation; D000813:Anilides / Q000737:chemistry* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D009636:Norbornanes / Q000737:chemistry; D011485:Protein Binding; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D003509:Cyclohexanecarboxylic Acids; D009636:Norbornanes; D018094:Receptors, Metabotropic Glutamate; C544970:VU 0155041; C044895:cyclohexanecarboxylic acid; C108823:metabotropic glutamate receptor 4
keywords: GPCRs; allosteric modulators; conformational probes; metabotropic glutamate receptors; norbornanes