Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists.
Chemical modification of the bicyclo[3.1.0]hexane ring C-3 position led to the discovery of 3-alkoxy-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 3-benzylthio-, and 3-benzylamino-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, metabotropic glutamate receptor 2 (mGluR2) antagonists. In particular, 3-(3,4-dichlorobenzyloxy)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15ae), (1R,2S,5R,6R)-2-amino-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic acid (15at), and (1R,2S,5R,6R)-2-amino-3-(N-(3,4-dichlorobenzylamino))-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic (15ba) showed high affinity for the mGluR2 receptor (15ae: K(i) = 2.51 nM, 15at: K(i) = 1.96 nM, and 15ba: K(i) = 3.29 nM) and potent antagonist activity for mGluR2 (15ae; IC50 = 34.21 nM, 15at; IC50 = 13.34 nM, and 15ba; IC50 = 35.96 nM). No significant agonist activity for mGluR2 was observed with 15ae, 15at, or 15ba. This paper reports on the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Yasuhara
Akito
A
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan. a.yasuhara@po.rd.taisho.co.jp
Sakagami
Kazunari
K
Yoshikawa
Ryoko
R
Chaki
Shigeyuki
S
Nakamura
Masato
M
Nakazato
Atsuro
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry; D001667:Binding, Competitive / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C104753:eglumetad