Profiling of trans-azetidine-2,4-dicarboxylic acid at the human metabotropic glutamate receptors mGlu_1b, -₂, -_4a and -_5a

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, mGlu₂, mGlu_4a and mGlu_5a expressed in mammalian cells. In Chinese hamster ovary (CHO) cells expressing human mGlu₂ 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 mGlu₂ 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 mGlu₂ receptor agonist and that (2R,4R)-azetidine-2,4-dicarboxylic acid is inactive at human mGlu₂ 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.