Photoisomerization of fluvoxamine generates an isomer that has reduced activity on the 5-hydroxytryptamine transporter and does not affect cell proliferation.
Fluvoxamine, a selective serotonin re-uptake inhibitor, is used as antidepressant/anxiolytic. The presence of a C=N double bond in the structure of fluvoxamine implies the existence of two geometric isomers: E- (trans) and Z- (cis), and suggests the hypothetical susceptibility of the molecule to photoisomerization. Clinically effective fluvoxamine is in its trans form. UVB (ultraviolet light, class B, wavelength range 290-320 nm) irradiation of aqueous solutions of fluvoxamine generated a photoproduct, which was isolated and analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS), and identified as the cis isomer of fluvoxamine. This cis-isomer lost capacity to inhibit serotonin uptake, suggesting that light exposure might reduce the clinical efficacy of fluvoxamine. Alternatively, the photoproduct could be used as an inactive isomer in the studies of antidepressant mechanisms. Recent proposal suggests that antidepressants increase neurogenesis in the adult brain, whereas either an inhibitory or a stimulatory action of antidepressants on [(3)H]thymidine uptake in vitro has been attributed to their interaction with serotonergic mechanisms. Lower concentrations (i.e., 2 microM) of fluvoxamine and fluoxetine (another selective serotonin re-uptake inhibitor) stimulated [(3)H]thymidine uptake in mature, but inhibited it in immature cultures of rat cerebellar granule cells; the photoproduct was ineffective. A high concentration of fluvoxamine (i.e., 20 microM) but not the photoproduct was toxic to both immature and mature cultures. We suggest that a mechanism sensitive to fluvoxamine photoisomerization might be involved in the action of antidepressants on cell proliferation.
Department of Pharmaceutical Sciences, Padova University, 35131 Padua, Italy.
Giorgia
G
Miolo
Sergio
S
Caffieri
Laura
L
Levorato
Marta
M
Imbesi
Pietro
P
Giusti
Tolga
T
Uz
Radmila
R
Manev
Hari
H
Manev
D000818:Animals; D000831:Animals, Newborn; D018687:Antidepressive Agents, Second-Generation / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects; D001921:Brain / Q000166:cytology / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004355:Drug Stability; D005473:Fluoxetine / Q000737:chemistry; D016666:Fluvoxamine / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects; D066298:In Vitro Techniques; D008297:Male; D010777:Photochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014466:Ultraviolet Rays
D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D012701:Serotonin; D016666:Fluvoxamine