Conformationally Restricted Homotryptamines. Part 7: 3-cis-(3-Aminocyclopentyl)indoles As Potent Selective Serotonin Reuptake Inhibitors
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- 作者：H. Dalton King ; Zhaoxing Meng ; Jeffrey A. Deskus ; Charles P. Sloan ; Qi Gao ; Brett R. Beno ; Edward S. Kozlowski ; Melissa A. LaPaglia ; Gail K. Mattson ; Thaddeus F. Molski ; Matthew T. Taber ; Nicholas J.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：November 11, 2010
- 年：2010
- 卷：53
- 期：21
- 页码：7564-7572
- 全文大小：928K
- 年卷期：v.53,no.21(November 11, 2010)
- ISSN：1520-4804
文摘
A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4−9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.