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
Ja. Monn et al., 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, J MED CHEM, 42(6), 1999, pp. 1027-1040
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.