Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors.
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.
King
H Dalton
HD
Bristol Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States. dalton.king@bms.com
Meng
Zhaoxing
Z
Deskus
Jeffrey A
JA
Sloan
Charles P
CP
Gao
Qi
Q
Beno
Brett R
BR
Kozlowski
Edward S
ES
Lapaglia
Melissa A
MA
Mattson
Gail K
GK
Molski
Thaddeus F
TF
Taber
Matthew T
MT
Lodge
Nicholas J
NJ
Mattson
Ronald J
RJ
Macor
John E
JE
D000818:Animals; D001682:Biological Availability; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D017551:Microdialysis; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D003517:Cyclopentanes; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014363:Tryptamines; C493230:SLC6A4 protein, human