| Abstract
| - Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), inwhich the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units,has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs).The (S)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. Wehave now synthesized the (S)- and (R)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPAreceptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs asrepresented by the mGluR2 subtype. The activities of (S)- and (R)-7 are rationalized byconformational analysis, comparison with the potent and specific group II mGluR agonist (−)-LY379268 [(−)-12], and docking to a homology model of mGluR2.
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