Differences in Agonist Binding Pattern for the GABAA and the AMPA Receptors Illustrated by High-Level AB Initio Calculations

A Novel Class of Potent 3-Isoxazolol GABAAAntagonists: Design, Synthesis, and Pharmacology

“…To overcome the problems of the structural relationships of the bioactive conformations and the receptor binding modes of 2 and 5 , it was envisaged that an arginine residue is a suitable binding partner to the carboxylate group of the endogenous ligand, GABA ( 1 ), as well as to the 3-isoxazolol anions of 2 and 3 . High-level quantum chemical ab initio calculations show that a bidentate interaction between the arginine side chain and the ligand is compatible with observed SARs . The involvement of an arginine residue in the binding of muscimol has recently been demonstrated by site-directed mutagenesis studies. − …”

“…Highlevel quantum chemical ab initio calculations show that a bidentate interaction between the arginine side chain and the ligand is compatible with observed SARs. 24 The involvement of an arginine residue in the binding of muscimol has recently been demonstrated by sitedirected mutagenesis studies. [25][26][27] The flexibility of the arginine side chain makes it feasible to accommodate 2 and 5 in the same binding pocket by assuming that the side chain adopts different conformations in its binding to the two ligands, as schematically illustrated in Figure 2a.…”

GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

“…A pharmacophore model that overcomes these problems has been developed [89,112,113] by noting that an arginine residue is a suitable binding partner to the carboxylate group of the endogenous ligand GABA, as well as to the 3-isoxazolol anions of muscimol (18), THIP (19), and 4-PIOL (24). High-level quantum chemical ab initio calculations show that a bidentate interaction between the arginine side chain and the ligand is compatible with observed SARs [114]. The involvement of an arginine residue in the binding of muscimol (18) has been demonstrated by site-directed mutagenesis studies [115][116][117].…”

“…The dissociative anesthetics PCP (114) and ketamine (115) block the NMDA receptor channel in a use-dependent manner [274] (Fig. 22).…”

“…Structures of some uncompetitive(114)(115)(116)(117)(118)(119)(120)(121) and noncompetitive(122)(123)(124)(125)(126) NMDA receptor antagonists.…”