DESIGN, SYNTHESIS, AND PHARMACOLOGICAL CHARACTERIZATION OF (-2-AMINOBICYCLO[3.1.0]HEXANE-2,6-DICARBOXYLIC ACID (LY354740) - A POTENT, SELECTIVE, AND ORALLY-ACTIVE GROUP-2 METABOTROPIC GLUTAMATE-RECEPTOR AGONIST POSSESSING ANTICONVULSANT AND ANXIOLYTIC PROPERTIES())

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau(1) and tau(2)) which determine the relative posit ions of the alpha-amino acid and distal carboxyl functionalities are c onstrained where tau(1) = 166.9 degrees or 202 degrees and tau(2) = 15 6 degrees, respectively. We hypothesized that 9 would closely approxim ate the proposed bioactive conformation of glutamate when acting at gr oup 2 metabotropic glutamate receptors (mGluRs). The racemic target mo lecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)- 9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stere ocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hy pothesis that 9 could interact with high affinity and specificity at g roup 2 mGluRs has been supported by the observation that (+/-)-9 (EC(5 0) = 0.086 +/- 0.025 mu M) and its enantiomer (=)-9 (EC(50) = 0.055 +/ - 0.017 mu M) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimula ted cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 mu M. Impo rtantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiet y (ED(50) = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (E D(50) = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mG luR agonist described thus far and is an important tool for studying t he effects of compounds of this class in humans.