M. Brian Arnold

[3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells

Metabotropic glutamate (mGlu) receptors are a family of eight known subtypes termed mGlu1-8. Currently, few ligands are available to study the pharmacology of mGlu receptor subtypes. In functional assays, we previously described LY341495 as a highly potent and selective mGlu2 and mGlu3 receptor antagonist. In this study, radiolabeled [3H]-LY341495 was used to investigate the characteristics of receptor binding to membranes from cells expressing human mGlu receptor subtypes. Using membranes from cells expressing human mGlu2 and mGlu3 receptors, [3H]-LY341495 (1 nM) specific binding was > 90% of total binding. At an approximate K(D) concentration for [3H]-LY341495 binding to human mGlu2 and mGlu3 receptors (1 nM), no appreciable specific binding of [3H-]LY341495 was found in membranes of cells expressing human mGlu1a, mGlu5a, mGlu4a, mGlu6, or mGlu7a receptors. However, modest (approximately 20% of mGlu2/3) specific [3H]-LY341495 (1 nM) binding was observed in human mGlu8 expressing cells. [3H]-LY341495 bound to membranes expressing human mGlu2 and mGlu3 receptors in a reversible and saturable manner with relatively high affinities (Bmax 20.5 +/- 5.4 and 32.0 +/- 7.0 pmol/mg protein; and K(D) = 1.67 +/- 0.20 and 0.75 +/- 0.43 nM, respectively). The pharmacology of [3H]-LY341495 binding in mGlu2 and mGlu3 expressing cells was consistent with that previously described for LY341495 in functional assays. [3H]-LY341495 binding provides a useful way to further investigate regulation of receptor expression and pharmacological properties of mGlu2 and mGlu3 receptor subtypes in recombinant systems.

[3H]LY341495, a highly potent, selective and novel radioligand for labeling group II metabotropic glutamate receptors

We report herein the synthesis and pharmacological characterization of a tritiated version of the potent and selective cyclopropyl amino acid LY341495 as a radioligand to label group II metabotropic glutamate receptors in rat brain homogenates.

Tetrazole amino acids as competitive NMDA antagonists

We describe here the synthesis and pharmacological characterization of two novel series of acidic amino acids (tetrazole-substituted acyclic amino acids and piperazine-2-carboxylic acids) as potential NMDA receptor antagonists. Potent, systemically active NMDA antagonists were discovered in the series of tetrazole-substituted piperazine-2-carboxylic acids.

Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists

We report the synthesis and characterization of compounds that are competitive NMDA receptor antagonists. Significant increases in affinity and potency were obtained by incorporation of a heteroatom into the substructure of the tetrazole-substituted amino acid LY233053.

Unusual stereochemical preferences of decahydroisoquinoline-3-cargoxylic acid competitive NMDA antagonists

Abstract We report the synthesis and characterization of the enantiomers of some C-6 epimeric tetrazole- and phosphonic acid-substituted decahydroisoquinoline competitive NMDA antagonists. We found that the absolute stereochemistry of the amino acid center was different for the active enantiomers of each C-6 epimer.

Synthesis and Characterization of Phosphonic Acid-Substituted Amino Acids as Excitatory Amino Acid Receptor Antagonists

Abstract Decahydroisoquinoline-3-carboxylic acids, substituted at C-6 with an acidic moiety such as a phosphonic, sulfonic or carboxylic acid or tetrazole, were prepared as antagonists of excitatory amino acid (EAA) receptors.