title: 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 mGlu1b, mGlu2, mGlu4a and mGlu5a expressed in mammalian cells. In Chinese hamster ovary (CHO) cells expressing human mGlu2 receptors, 500 microM (2S,4S)-ADA inhibited forskolin-stimulated cAMP accumulation by 33 +/- 3% while 100 microM (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 mGlu4a receptors, 10 microM L-AP4 inhibited forskolin-stimulated cAMP levels by 37 +/- 4% whereas both ADA enantiomers of trans-azetidine-2,4-dicarboxylic acid (500 microM) had no such effect. In CHO cells expressing human mGlu1b receptors and L cells expressing human mGlu5a receptors, both enantiomers, applied at 500 microM 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 mGlu4a receptors and neither agonistic nor antagonistic effects on human mGlu1b and mGlu5a receptors.
authors.affiliation: CNS Research, Ciba, Basle, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Knöpfel
authors.forename: J
authors.initials: J
authors.lastname: Sakaki
authors.forename: P J
authors.initials: PJ
authors.lastname: Flor
authors.forename: P
authors.initials: P
authors.lastname: Baumann
authors.forename: A I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: G
authors.initials: G
authors.lastname: Veliçelebi
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.forename: H
authors.initials: H
authors.lastname: Allgeier
mesh_terms: D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D018094:Receptors, Metabotropic Glutamate; C083095:azetidine-2,4-dicarboxylic acid; D001383:Azetidinecarboxylic Acid; D000242:Cyclic AMP