Yasuhara Akito, Sakagami Kazunari, Yoshikawa Ryoko, Chaki Shigeyuki, Nakamura Masato, Nakazato Atsuro
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
Bioorg Med Chem. 2006 May 15;14(10):3405-20. doi: 10.1016/j.bmc.2005.12.061. Epub 2006 Jan 20.
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.
对双环[3.1.0]己烷环的C-3位进行化学修饰，从而发现了3-烷氧基-2-氨基双环[3.1.0]己烷-2,6-二羧酸、3-苄硫基-和3-苄氨基-2-氨基-6-氟双环[3.1.0]己烷-2,6-二羧酸衍生物，即代谢型谷氨酸受体2（mGluR2）拮抗剂。特别是，3-(3,4-二氯苄氧基)-2-氨基双环[3.1.0]己烷-2,6-二羧酸（15ae）、(1R,2S,5R,6R)-2-氨基-3-(3,4-二氯苄硫基)-6-氟双环[3.1.0]己烷-2,6-二羧酸（15at）和(1R,2S,5R,6R)-2-氨基-3-(N-(3,4-二氯苄氨基))-6-氟双环[3.1.0]己烷-2,6-二羧酸（15ba）对mGluR2受体表现出高亲和力（15ae：K(i)=2.51 nM，15at：K(i)=1.96 nM，15ba：K(i)=3.29 nM），并且对mGluR2具有强效拮抗活性（15ae；IC50=
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