Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose–response similar to the SSRI fluoxetine in microdialysis studies in rats.

Graphical abstractA series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, compound 6a gave potent SERT activity. The enantiomers of 6a were energy minimized and compared to other known conformationally restricted SSRIs. Compound 6a was also found to give a dose–response similar to the SSRI fluoxetine in microdialysis studies in rats.Figure optionsDownload full-size imageDownload as PowerPoint slide