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.
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.
Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Christo
C
Christov
Patricia
P
González-Bulnes
Fanny
F
Malhaire
Tatyana
T
Karabencheva
Cyril
C
Goudet
Jean-Philippe
JP
Pin
Amadeu
A
Llebaria
Jesús
J
Giraldo
D000494:Allosteric Regulation / Q000187:drug effects*; D001665:Binding Sites; D002460:Cell Line; D002942:Circular Dichroism; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D013237:Stereoisomerism
D003509:Cyclohexanecarboxylic Acids; D018094:Receptors, Metabotropic Glutamate; C044895:cyclohexanecarboxylic acid; C108823:metabotropic glutamate receptor 4