Ligand conformation has a definitive effect on 5-HT1A and serotonin reuptake affinity.
Conformationally constrained aryl cyclohexanes and cyclohexenes based on aryl cyclohexanols 1 were prepared. Locking the aryl ring in plane with the cyclohexane moiety provided potent SSRIs 3. Conversely, fixing the aryl ring perpendicular to the cyclohexane ring via a spiro lactone provided balanced 5-HT1A antagonists with mid-nanomolar range SSRI potency (compounds 2).
Boy
Kenneth M
KM
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. boyk@bms.com
Dee
Michael
M
Yevich
Joseph
J
Torrente
John
J
Gao
Qi
Q
Iben
Lawrence
L
Stark
Arlene
A
Mattson
Ronald J
RJ
D008024:Ligands; D008968:Molecular Conformation; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000378:metabolism*
D008024:Ligands; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors