Profiling of trans-azetidine-2,4-dicarboxylic acid at the human metabotropic glutamate receptors mGlu1b, -2, -4a and -5a.

Abstract We have tested the two enantiomers of trans-azetidine-2,4-dicarboxylic acid, (2S,4S)-azetidine-2,4-dicarboxylic acid ((2S,4S)-ADA) and (2R,4R)-azetidine-2,4-dicarboxylic acid ((2R,4R)-ADA) for activity at the human metabotropic glutamate receptors mGlu 1b , mGlu 2 , mGlu 4a and mGlu 5a expressed in mammalian cells. In Chinese hamster ovary (CHO) cells expressing human mGlu 2 receptors, 500 μM (2S,4S)-ADA inhibited forskolin-stimulated cAMP accumulation by 33±3% while 100 μM (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid induced an inhibition by 66±5%. The (2R,4R)-ADA enantiomer was inactive at human mGlu 2 receptors. In CHO cells expressing human mGlu 4a receptors, 10 μM L-AP4 inhibited forskolin-stimulated cAMP levels by 37±4% whereas both ADA enantiomers of trans-azetidine-2,4-dicarboxylic acid (500 μM) had no such effect. In CHO cells expressing human mGlu 5a receptors and L cells expressing human mGlu 5a receptors, both enantiomers, applied at 500 μM or 1 mM, were ineffective in stimulating inositolmonophosphate accumulation and did not affect quisqualate-stimulated inositolmonophosphate accumulation. We conclude that (2S,4S)-azetidine-2,4-dicarboxylic acid is a weak human mGlu 2 receptor agonist and that (2R,4R)-azetidine-2,4-dicarboxylic acid is inactive at human mGlu 2 receptors. Trans-azetidine-2,4-dicarboxylic acid has no significant agonistic effect on human mGlu 4a receptors and neither agonistic nor antagonistic effects on human mGlu 1b and mGlu 5a receptors.