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

• Published in: Journal of medicinal chemistry Vol. 43; no. 25; pp. 4893 - 4909
• Main Authors: Nakazato, Atsuro, Kumagai, Toshihito, Sakagami, Kazunari, Yoshikawa, Ryoko, Suzuki, Yoshiko, Chaki, Shigeyuki, Ito, Hisanaka, Taguchi, Takeo, Nakanishi, Shigetada, Okuyama, Shigeru
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2000; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Calcium - metabolism; Chemistry, Medicinal; CHO Cells; Cricetinae; Crystallography, X-Ray; Cyclic AMP - biosynthesis; Dicarboxylic Acids - chemical synthesis; Dicarboxylic Acids - chemistry; Dicarboxylic Acids - pharmacology; Excitatory Amino Acid Agonists - chemical synthesis; Excitatory Amino Acid Agonists - chemistry; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Inositol 1,4,5-Trisphosphate - biosynthesis; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, Metabotropic Glutamate - agonists; Schizophrenia - drug therapy; Science & Technology; Stereoisomerism; Structure-Activity Relationship; LY354740; PHENCYCLIDINE; CELLS; CORTICAL-NEURONS; ESTERS; RATS; BRAIN-FUNCTION; MOLECULAR DIVERSITY; FAMILY; Human; Molecular rigidity; Agonist; Neuroleptic; Psychotropic; Oral administration; Schizophrenia; Glutamate receptor; Selectivity; α-Aminoacid; Structure activity relation; Metabotropic receptor; Fluorine Organic compounds; Ketoacid; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000346k

(+)-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:  K i = 47.7 ± 17 nM and 65.9 ± 7.1 nM for mGluR2 and mGluR3, respectively; 4:  K i = 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:  K i = 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 (K i = 0.570 ± 0.10 nM) and mGluR3 (K i = 2.07 ± 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K i = >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.