NO-SSRIs: Nitric oxide chimera drugs incorporating a selective serotonin reuptake inhibitor

Samer Abdul-Hay, Isaac T. Schiefer, R. Esala P. Chandrasena, Min Li, Ramy Abdelhamid, Yue Ting Wang, Ehsan Tavassoli, Bradley Michalsen, Rezene T. Asghodom, Jia Luo, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 h. 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) were 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 cotherapy of neuropathologies concomitant with depression.

Original languageEnglish (US)
Pages (from-to)656-661
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume2
Issue number9
DOIs
StatePublished - Sep 8 2011
Externally publishedYes

Keywords

  • SSRI
  • antidepressant
  • cognition
  • hybrid drug
  • nitrate
  • nitric oxide

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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