PROFILING OF TRANS-AZETIDINE-2,4-DICARBOXYLIC ACID AT THE HUMAN METABOTROPIC GLUTAMATE RECEPTORS MGLU(1B), MGLU(2), MGLU(4), AND MGLU(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,4 R)-azetidine-2,4-dicarboxylic acid ((2R,4R)-ADA) for activity at the h uman 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 mu M (2S,4S)-ADA inhibit ed forskolin-stimulated cAMP accumulation by 33 +/- 3% while 100 mu M (1S,3R)-1-Aminocyclopentane-1,3-dicarboxlic 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 mu M L-AP4 inhibited forskolin-stimulated cAMP levels by 37 +/- 4% whereas both ADA enantiomers of trans-azetidine-2,4-dicarboxylic acid (500 mu M) had no such effect. In CHO cells expressing human mGlu(1b) recepto rs and L cells expressing human mGlu(5a) receptors, both enantiomers, applied at 500 mu M or 1 mM, were ineffective in stimulating inositolm onophosphate accumulation and did not affect quisqualate-stimulated in ositolmonophosphate 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 in active at human mGlu(2) receptors. Trans-azetidine-2,4-dicarboxylic acid has no significant a gonistic effect on human mGlu(4a) receptors and neither agonistic nor antagonistic effects on human mGlu(1b) and mGlu(5a) receptors.