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Exploring the Active Conformation of Cyclohexane Carboxylate Positive Allosteric Modulators of the Type 4 Metabotropic Glutamate Receptor
Author(s) -
Rovira Xavier,
Harrak Youssef,
Trapero Ana,
GonzálezBulnes Patricia,
Malhaire Fanny,
Pin JeanPhilippe,
Goudet Cyril,
Giraldo Jesús,
Llebaria Amadeu
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402190
Subject(s) - pharmacophore , chemistry , stereochemistry , metabotropic glutamate receptor , cyclohexanecarboxylic acid , enantiomer , amide , allosteric regulation , substituent , metabotropic glutamate receptor 5 , glutamate receptor , receptor , biochemistry
The active conformation of a family of metabotropic glutamate receptor subtype 4 (mGlu 4 ) 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 mGlu 4 conformational probes and the enantiomers of the trans diastereomer were computationally characterized and tested in mGlu 4 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 mGlu 4 allosteric binding site, thus providing a step forward in structure‐based drug design for mGlu 4 PAMs.