| Abstract
| - As part of our ongoing research program aimed at the identification of highly potent, selective,and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, wehave prepared novel heterobicyclic amino acids (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268, (−)-9) and (−)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate(LY389795, (−)-10). Compounds (−)-9 and (−)-10 are structurally related to our previouslydescribed nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5being replaced with either an oxygen atom (as in (−)-9) or a sulfur atom (as in (−)-10).Compounds (−)-9 and (−)-10 potently and stereospecifically displaced specific binding of themGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displayingIC50 values of 15 ± 4 and 8.4 ± 0.8 nM, respectively, while having no effect up to 100 000 nMon radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors.Compounds (−)-9 and (−)-10 also potently displaced [3H]LY341495 binding from membranesexpressing recombinant human group II mGlu receptor subtypes: (−)-9, Ki = 14.1 ± 1.4 nMat mGlu2 and 5.8 ± 0.64 nM at mGlu3; (−)-10, Ki = 40.6 ± 3.7 nM at mGlu2 and 4.7 ± 1.2 nMat mGlu3. Evaluation of the functional effects of (−)-9 and (−)-10 on second-messengerresponses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated eachto be a highly potent agonist for group II mGlu receptors: (−)-9, EC50 = 2.69 ± 0.26 nM atmGlu2 and 4.58 ± 0.04 nM at mGlu3; (−)-10, EC50 = 3.91 ± 0.81 nM at mGlu2 and 7.63 ±2.08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonistor antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, ormGlu7a receptors. The agonist effects of (−)-9 and (−)-10 at group II mGlu receptors were nottotally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (−)-9 (EC50 = 401 ± 46 nM) and at micromolar concentrations (EC50 = 2 430 ± 600nM) for (−)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations(EC50 = 1 690 ± 130 and 7 340 ± 2 720 nM, respectively). Intraperitoneal administration ofeither (−)-9 or (−)-10 in the mouse resulted in a dose-related blockade of limbic seizure activityproduced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((−)-9 ED50 = 19mg/kg, (−)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbicexcitation. Thus, heterobicyclic amino acids (−)-9 and (−)-10 are novel pharmacological toolsuseful for exploring the functions of mGlu receptors in vitro and in vivo.
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