| Autor: |
Monn, J. A., Valli, M. J., Massey, S. M., Wright, R. A., Salhoff, C. R., Johnson, B. G., Howe, T., Alt, C. A., Rhodes, G. A., Robey, R. L., Griffey, K. R., Tizzano, J. P., Kallman, M. J., Helton, D. R., Schoepp, D. D. |
| Zdroj: |
Journal of Medicinal Chemistry; February 1997, Vol. 40 Issue: 4 p528-537, 10p |
| Abstrakt: |
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 (τ1 and τ2) which determine the relative positions of the α-amino acid and distal carboxyl functionalities are constrained where τ1 = 166.9° or 202° and τ 2 = 156°, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (±)-9, its C2-diastereomer (±)-16, and its enantiomers (+)-9 (LY354740) and (−)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (±)-9 (EC50 = 0.086 ± 0.025 μM) and its enantiomer (+)-9 (EC50 = 0.055 ± 0.017 μM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 μM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans. |
| Databáze: |
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