Characterization of [(3)H]Quisqualate binding to recombinant rat metabotropic glutamate 1a and 5a receptors and to rat and human brain sections.
ABSTRACT We have investigated the binding properties of [(3)H]quisqualate to rat metabotropic glutamate (mGlu) 1a and 5a receptors and to rat and human brain sections. Saturation isotherms gave K:(D) values of 27 +/- 4 and 81 +/- 22 nM: for mGlu1a and mGlu5a receptors, respectively. Several compounds inhibited the binding to mGlu1a and mGlu5a receptors concentration-dependently. (S:)-4-Carboxyphenylglycine, (S:)-4-carboxy-3-hydroxyphenylglycine, and (R,S)-1-aminoindan-1,5-dicarboxylic acid, which completely inhibited [(3)H]quisqualate binding to the mGlu5a receptor, were inactive in a functional assay using this receptor. The distribution and abundance of binding sites in rat and human brain sections were studied by quantitative receptor radioautography and image analysis. Using 10 nM: [(3)H]quisqualate, a high density of binding was detected in various brain regions with the following rank order of increasing levels: medulla, thalamus, olfactory bulb, cerebral cortex, spinal cord dorsal horn, olfactory tubercle, dentate gyrus molecular layer, CA1-3 oriens layer of hippocampus, striatum, and cerebellar molecular layer. The ionotropic component of this binding could be inhibited by 30 microM: kainate, revealing the distribution of mGlu1+5 receptors. The latter were almost completely inhibited by the group I agonist (S:)-3,5-dihydroxyphenylglycine. The binding profile correlated well with the cellular sites of synthesis and regional expression of the respective group I receptor proteins revealed by in situ hybridization histochemistry and immunohistochemistry, respectively.
Article: Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.[show abstract] [hide abstract]
ABSTRACT: Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.Journal of Medicinal Chemistry 10/2007; 50(19):4630-41. · 5.25 Impact Factor