Synthesis, SARs, and Pharmacological Characterization of 2-Amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Derivatives as Potent, Selective, and Orally Active Group II Metabotropic Glutamate Receptor Agonists

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Abstract
(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon−fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7−10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC50 = 29.4 ± 3.3 nM and 45.4 ± 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC50 = 18.3 ± 1.6 nM and 62.8 ± 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED50 = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivy and PCP-induced head-weaving behavior, respectively; 4: ED50 = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [3H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: Ki = 47.7 ± 17 nM and 65.9 ± 7.1 nM for mGluR2 and mGluR3, respectively; 4: Ki = 23.4 ± 7.1 nM and 53.5 ± 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R,6R)-2-Amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((−)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((−)-11: Ki = 16.6 ± 5.6 and 80.9 ± 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH2 at C4 position of compound 11, since replacement of the CH2 group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH2 at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH2 group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (Ki = 0.570 ± 0.10 nM) and mGluR3 (Ki = 2.07 ± 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (Ki = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED50 = 0.090 μg/kg) and hyperactivity (ED50 = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.