Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): Identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors

As part of our ongoing research program aimed at the identification of high ly potent, selective, and systemically active agonists for group II metabot ropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic ami no 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 (LY38 9795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our p reviously described nanomolar potency group II mGlu receptor agonist, (+)-2 -aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydr ate, 5), with the C4-methylene unit of 5 being replaced with either an oxyg en atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mG lu2/3 receptor antagonist ([H-3]LY341495) in rat cerebral cortical homogena tes, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, w hile having no effect up to 100000 nM on radioligand binding to the glutama te recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 an d (-)-10 also potently displaced [H-3]LY341495 binding from membranes expre ssing recombinant human group II mGlu receptor subtypes: (-)-9, K-i = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, K-i = 40.6 +/- 3. 7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional eff ects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly p otent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM a t mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at m Glu2 and 7.63 +/- 2.08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of(-)-9 and (-)-10 at group II mGlu receptors were not totally spe cific, however, as mGlu6 agonist activity was observed at high nanomolar co ncentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrati ons (EC50 = 2430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1690 +/- 130 and 7340 +/- 27 20 nM, respectively). Intraperitoneal administration of either (-)-9 or (-) -10 in the mouse resulted in a dose-related blockade of limbic seizure acti vity produced by the nonselective group I/group II mGluR agonist (1S,SR)-AC PD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these m olecules effectively cross the blood-brain barrier following systemic admin istration and suppress group I mGluR-mediated limbic excitation. Thus, hete robicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools use ful for exploring the functions of mGlu receptors in vitro and in vivo.