Journal of medicinal and pharmaceutical chemistry 2010-11-11

Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors.

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 Lodge, Ronald J Mattson, John E Macor

Index: J. Med. Chem. 53 , 7564, (2010)

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Abstract

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.