Molecular structure of fluoxetine hydrochloride, a highly selective serotonin-uptake inhibitor.
Fluoxetine, a selective inhibitor of serotonin uptake, is clinically useful in treating depression and may be useful for management of a variety of other psychiatric and metabolic derangements. Using X-ray crystallography, we have determined the three-dimensional structure of fluoxetine hydrochloride. A total of 2394 unique reflections were measured, and full-matrix least-squares refinement of all non-hydrogen coordinates and thermal parameters gave a final discrepancy index of 0.074 for 1759 observed reflections. In the solid state, the planes defined by the two aromatic rings are skewed, precluding the possibility of intramolecular ring-ring interactions. The methylene units of the methylpropanamine moiety adopt the anticipated conformational relationships to minimize torsional strain. An exact antiperiplanar relationship exists between N11 and C3; the N11-C1-C2-C3 dihedral angle is -180 degrees. The C1-C2-C3-O4 dihedral angle is 60.6 degrees, indicating that the propanamine side-chain folds toward the phenoxy moiety rather than adopting a fully extended conformation. This folded three-dimensional relationship may be necessary for high-affinity interaction with the serotonin-uptake carrier and confers considerable structural homology between this portion of fluoxetine and the phenylcyclohexylamine substructure of sertraline and EXP-561. However, the nature of substituents on the phenoxy portion of fluoxetine is also critical in determining potency and selectivity in this series of compounds.
Robertson
D W
DW
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
Jones
N D
ND
Swartzendruber
J K
JK
Yang
K S
KS
Wong
D T
DT
D000818:Animals; D001921:Brain / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009638:Norepinephrine / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014961:X-Ray Diffraction
D011437:Propylamines; D012702:Serotonin Antagonists; D005473:Fluoxetine; D012701:Serotonin; D009638:Norepinephrine