| Autor: |
Mattson, R. J., Catt, J. D., Denhart, D. J., Deskus, J. A., Ditta, J. L., Higgins, M. A., Marcin, L. R., Sloan, C. P., Beno, B. R., Gao, Q., Cunningham, M. A., Mattson, G. K., Molski, T. F., Taber, M. T., Lodge, N. J. |
| Zdroj: |
Journal of Medicinal Chemistry; September 2005, Vol. 48 Issue: 19 p6023-6034, 12p |
| Abstrakt: |
A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
