Search Results - (Author, Cooperation:T. J. Mangano)

2015-11-10

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Allosteric Regulation/drug effects ; Allosteric Site ; Animals ; Anti-Anxiety Agents/analysis/chemistry/metabolism/pharmacology ; Benzyl Alcohols/analysis/*chemistry/metabolism/*pharmacology ; Conditioning, Classical ; *Drug Discovery ; Fear ; Female ; HEK293 Cells ; Humans ; Ligands ; Lorazepam/analysis/*chemistry/metabolism/*pharmacology ; Male ; Memory/drug effects ; Mice ; Mice, Knockout ; Models, Molecular ; Receptors, G-Protein-Coupled/agonists/antagonists & ; inhibitors/chemistry/deficiency/*metabolism ; Signal Transduction/drug effects ; Triazines/analysis/*chemistry/metabolism/*pharmacology

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: HA-966 (1-hydroxy-3-aminopyrrolidone-2) is an antagonist at the glycine allosteric site of the N-methyl-d-aspartate receptor ionophore complex. Unlike presently known glycine antagonists, HA-966 is chiral. We report stereoselectivity for the (R)-enantiomer at the glycine antagonist site. In [3H]glycine binding, the (R)-enantiomer has an IC50 of 4.1 ± 0.6 μM. The racemic mixture has an IC50 of 11.2 ± 0.5 μM, whereas (S)-HA-966 has an IC50 greater than 900 μM. In glycine-stimulated [3H]l-[1-(2-thienyl)cyclohexyl] piperidine binding, the (R)-enantiomer inhibits with an IC50 of 121 ± 61μM, whereas the racemic mixture has an IC50 of 216 ± 113 μM and (S)-HA-966 is inactive. The inhibition by (R)-HA-966 can be prevented by the addition of glycine. (R)-HA-966 and racemic HA-966, but not (S) HA-966, also prevent N-methyl-d-aspartate cytotoxicity in cortical cultures. The (R)-enantiomer and, less potently, the (S)-enantiomer inhibit N-methyl-d-aspartate-evoked [3H]norepinephrine release from rat hippocampal slices (IC50 values of about 0.3 mM and 1.6 mM, respectively), but only the inhibition by (R)-HA-966 is reversed by added glycine. In glutamate-evoked contractions of the guinea pig ileum, (R)-HA-966 causes a glycine-reversible inhibition (IC50 of about 150 μM), whereas (S)-HA-966 is much less potent (IC50 of greater than 1mM). These results demonstrate stereoselectivity of the glycine antagonist site of the N-methyl-d-aspartate receptor complex in a variety of tissues and assays. The stereoselectivity also confirms the specificity of N-methyl-d-aspartate receptors in glutamate-evoked contractions of the guinea pig ileum, and supports their similarity to central N-methyl-d-aspartate receptors.

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