Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABAC receptors

Abstract

The enantiomers of 3F-GABA were evaluated on GABA(C) receptors. Both enantiomers were agonists, with the (R)-enantiomer being an order of magnitude more potent. This result is consistent with a folded binding mode for GABA, a conclusion which suggests a different binding mode to that found in the related but pharmacologically distinct GABA(A) receptors.

Differentiating Enantioselective Actions of GABOB: A Possible Role for Threonine 244 in the Binding Site of GABAC ρ1 Receptors

“…Altered GABA sensitivity indicates either a change in GABA binding for the orthosteric binding site or a change in receptor gating. Homology modeling predicts that the acidic group of GABA may form a H-bond with the hydroxyl group of T244, 29 indicating that the change in GABA potency observed at the ρ 1 T244S mutant is the result of altered binding. However, there are many limitations to inferences derived from homology modeling, particularly with respect to conformational changes that occur throughout the structure initiated by ligand binding leading to channel opening.…”

“…Our previous homology modeling studies 26,29 have shown the possible formation of H-bonds between S243 or T244 with the carboxylate group of GABA. Modeling studies with GABOB show the possible formation of a H-bond with the hydroxyl group of GABOB.…”

“…This residue is highly conserved in chloride selective Cys-loop receptors, such as the GABA A/C and glycine receptors. 27,28 Our homology model predicts a possible hydrogen-bond (H-bond) formation between the acidic group of GABA and the hydroxyl group of T244 29 and a possible H-bond between the C3-hydroxyl group of GABOB and T244 (Figure 2). In addition, the model predicts there are no H-bonds between the C3-hydroxyl group of the phosphinic analogue of GABOB, S-and R-(3-amino-2-hydroxypropyl)-methylphosphinic acid (S-(−)-CGP44532 and R-(+)-CGP44533) and T244 ( Figure 2).…”

The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems

“…18 [ 156 , 157 ]. Both fluorinated derivatives were agonists at ρ1 and ρ2 GABA C receptors, with the ( R )-isomer 97 tenfold weaker and the ( S )-isomer 96 20-fold weaker than the natural ligand 95 [ 158 ]. This was attributed to weaker electrostatic interactions due to the reduced basicity of the amine, observations that taken together suggested that GABA ( 95 ) binds to the GABA C receptor in the folded orientation represented by conformation C in Fig.…”

3‐Fluoro‐N‐methyl‐D‐aspartic acid (3F‐NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA Receptors

“…Previously, we have prepared separate enantiomers of 3‐fluoro‐γ‐aminobutyric acid (3F‐GABA) ( 6 ) to probe the chirality of γ‐aminobutyric acid (GABA) ( 5 ) binding to both GABA A and GABA C receptors 14. 15, 16 In those studies we observed significantly different efficacies for the two enantiomers ( R )‐ 6 and ( S )‐ 6 suggesting that the GABA A and GABA C receptors bind γ‐aminobutyric acid in different conformations. The conformational bias was attributed to the electrostatic charge–dipole interaction between the CF and CN + bonds as illustrated in Figure 1, thus the different enantiomers of 3F‐GABA can adopt preferred twisted conformations of the opposite chiral sense, and a favoured binding mode was deduced by comparing the efficacy of the two enantiomers of 3F‐GABA ( 6 ).…”