TY - JOUR
T1 - Integrated Synthetic, Pharmacological, and Computational Investigation of cis-2-(3,5-Dichlorophenylcarbamoyl) cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4
AU - Christov, Christo
AU - González-Bulnes, Patricia
AU - Malhaire, Fanny
AU - Karabencheva-Christova, Tatyana
AU - Goudet, Cyril
AU - Pin, Jean-Philippe
AU - Llebaria, Amadeu
AU - Giraldo, Jesús
PY - 2011/1/3
Y1 - 2011/1/3
N2 - 2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol. 2008, 74, 1345-1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High-level quantum chemical calculations were carried out to characterize the structures of minimum energy in all-isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R, 2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R, 2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.
AB - 2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol. 2008, 74, 1345-1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High-level quantum chemical calculations were carried out to characterize the structures of minimum energy in all-isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R, 2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R, 2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.
KW - allosteric modulators
KW - computational chemistry
KW - enantioselectivity
KW - G-protein-coupled receptors
KW - mGluR4
U2 - 10.1002/cmdc.201000378
DO - 10.1002/cmdc.201000378
M3 - Article
SN - 1860-7179
VL - 6
SP - 131
EP - 140
JO - ChemMedChem
JF - ChemMedChem
IS - 1
ER -