Exploring the Active Conformation of Cyclohexane Carboxylate Positive Allosteric Modulators of the Type 4 Metabotropic Glutamate Receptor. Issue 12 (5th September 2014)

• Record Type: Journal Article
• Authors: Rovira, Xavier; Harrak, Youssef; Trapero, Ana; González‐Bulnes, Patricia; Malhaire, Fanny; Pin, Jean‐Philippe; Goudet, Cyril; Giraldo, Jesús; Llebaria, Amadeu
• Is Part Of: ChemMedChem. Volume 9:Issue 12(2014:Dec.)
• Page Start: 2685
• Page End: 2698
• Publication Date: 2014-09-05
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402190
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>cis</italic>‐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 <italic>trans</italic> 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.</p> </abstract>