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.
Deskus
Jeffrey A
JA
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. jeffrey.deskus@bms.com
Epperson
James R
JR
Sloan
Charles P
CP
Cipollina
Joseph A
JA
Dextraze
Pierre
P
Qian-Cutrone
Jingfang
J
Gao
Qi
Q
Ma
Baoqing
B
Beno
Brett R
BR
Mattson
Gail K
GK
Molski
Thaddeus F
TF
Krause
Rudolph G
RG
Taber
Matthew T
MT
Lodge
Nicholas J
NJ
Mattson
Ronald J
RJ
D000818:Animals; D053138:Cyclohexenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005473:Fluoxetine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017551:Microdialysis; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D014363:Tryptamines / Q000737:chemistry*
D053138:Cyclohexenes; D005473:Fluoxetine; D007211:Indoles; D011725:Pyridines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014363:Tryptamines; C493230:SLC6A4 protein, human