Synthesis, in Vitro Pharmacology, Structure−Activity Relationships, and Pharmacokinetics of 3-Alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Derivatives as Potent and Selective Group II Metabotropic Glutamate Receptor Antagonists

Abstract

Novel group II metabotropic glutamate receptor (mGluR) antagonists, 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, were discovered by the incorporation of a hydroxy or alkoxyl group onto the C-3 portion of selective and potent group II mGluR agonist 5, (1R,2S,5R,6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Among these compounds, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (-)-11be (MGS0039) was a highly selective and potent group II mGluR antagonist with the best pharmacokinetic profile. Compound (-)-11be exhibited high affinities for mGlu 2 (Ki = 2.38 +/- 0.40 nM) and mGlu 3 (4.46 +/- 0.31 nM) but low affinity for mGluR 7 (Ki = 664 +/- 106 nM), and potent antagonist activities for mGlu 2 (IC50 = 20.0 +/- 3.67 nM) and mGluR 3 (IC50 = 24.0 +/- 3.54 nM) but much less potent antagonist activities for mGlu 4 (IC50 = 1740 +/- 1080 nM), mGlu 6 (IC50 = 2060 +/- 1270 nM), mGlu 1 (IC50 = 93300 +/- 14600 nM), and mGluR 5 (IC(50) = 117000 +/- 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100,000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma C(max): 214 +/- 56.7, 932 +/- 235, and 2960 +/- 1150 ng/mL for 3 mg/kg, 10 mg/kg, and 30 mg/kg, po, respectively) and acceptable blood-brain barrier penetration (brain C(max): 13.2 ng/mL for 10 mg/kg, p.o. 6 h). In this paper, we report the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, and pharmacokinetic profiles of several typical compounds.

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…LY341495 has nanomolar affinities for mGlu 2/3 receptors [109,110]. MGS0039 containing a bicyclo[3.1.0]hexane ring system was reported to have nanomolar affinities for mGlu 2/3 receptors [111]. The series of mGlu 2/3 receptors antagonists that have amino acid moieties are found at low levels in the CNS.…”

In Vitro and in Vivo Evaluation of the Metabolism and Bioavailability of Ester Prodrugs of Mgs0039 (3-(3,4-DICHLOROBENZYLOXY)-2-AMINO-6-FLUOROBICYCLO[3.1.0]HEXANE-2,6-DICARBOXYLIC Acid), a Potent Metabotropic Glutamate Receptor Antagonist

“…MGS0039, its prodrugs ( Fig. 1), and MG0037 (3-(3,4-difluorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid) (internal standard) were synthesized in Taisho Research Laboratories as described previously (Nakazato et al, 2004). NADP ϩ and glucose 6-phosphate were obtained from Oriental Yeast Co., Ltd. (Tokyo, Japan).…”

“…MGS0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid) is a potent and selective antagonist for group II mGluRs as determined by attenuation of glutamateinduced inhibition of forskolin-evoked cAMP formation in Chinese hamster ovary cells expressing mGluR2 (IC 50 ϭ 20 nM) or mGluR3 (IC 50 ϭ 24 nM) Nakazato et al, 2004). We previously reported that group II mGluR antagonists exhibited antidepressant potential in experimental animal models such as the rat forced swimming and mouse tail suspension tests .…”

“…We previously reported that group II mGluR antagonists exhibited antidepressant potential in experimental animal models such as the rat forced swimming and mouse tail suspension tests . Moreover, we recently reported on the synthesis, in vitro pharmacological profiles, structure-activity relationships, and pharmacokinetics profiles of group II mGluR antagonists (Nakazato et al, 2004). After oral dosing in rats, MGS0039 exhibited higher plasma and brain concentrations than did (2S)-amino-2-((1S,2S)-2-carboxycycloprop-1-yl)-3-(9-xanthyl)propionic acid (LY341495) (Ornstein et al, 1998a,b), whereas oral bioavailability was 10.9% (Levine et al, 2002).…”

Depression Viewed as a GABA/Glutamate Imbalance in the Central Nervous System

“…Table 3 a number of experiments described the antidepressant-like activity of ligands of the mGlu 2/3 receptors. The best known selective and brain penetrating ligands of mGlu 2/3 receptors is MGS0039 (Nakazato et al, 2004). Another antagonist LY341495, is able to bind the third group of mGlu receptors too (Chung et al, 1997).…”