title: NO-SSRIs: Nitric Oxide Chimera Drugs Incorporating a Selective Serotonin Reuptake Inhibitor.
abstract: Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 hours. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter, however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061), was made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide co-therapy of neuropathologies concomitant with depression.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612-7231.
authors.forename: Samer
authors.initials: S
authors.lastname: Abdul-Hay
authors.forename: Isaac T
authors.initials: IT
authors.lastname: Schiefer
authors.forename: R Esala P
authors.initials: RE
authors.lastname: Chandrasena
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Ramy
authors.initials: R
authors.lastname: Abdelhamid
authors.forename: Yue-Ting
authors.initials: YT
authors.lastname: Wang
authors.forename: Ehsan
authors.initials: E
authors.lastname: Tavassoli
authors.forename: Bradley
authors.initials: B
authors.lastname: Michalsen
authors.forename: Rezene T
authors.initials: RT
authors.lastname: Asghodom
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher