2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors

Troy Voelker, Haiji Xia, Keith Fandrick, Robert Johnson, Aaron Janowsky, John R. Cashman

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Enhancement of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission is a viable means of treating depression. On the basis of this observation, agents that inhibit re-uptake of 5-HT were prepared based on (-)-cocaine and aryltropanes as lead compounds because they are reasonably potent 5-HT re-uptake inhibitors. Molecular dissection of an aryltropane provided a series of 5- and 6-membered ring compounds. From among this library of compounds a series of disubstituted tetrahydrofurans bearing 2-alkyl aryl and 5-alkyl amino groups were identified as having highly potent and selective 5-HT re-uptake inhibition. The compounds were evaluated for their ability to compete with radiolabeled RTI-55 binding and to inhibit re-uptake of neurotransmitters at the human dopamine, serotonin and norepinephrine transporters. Based on potency (e.g., Ki = 800 pM) and significant functional selectivity (e.g., IC50 ratios for human dopamine:serotonin or norepinephrine:serotonin, ≥1397) highly potent and selective serotonin re-uptake inhibitors were identified. Optimal features playing a dominant role in binding affinity and re-uptake inhibition included lipophilic substitution on the aromatic moiety, trans relative stereochemistry of the 2,5-disubstituted tetrahydrofuran ring, and a total of four or five methylene groups between the alkyl amine and the alkyl aryl moiety and the tetrahydrofuran group. A number of the most potent serotonin re-uptake inhibitors were tested in Balb/c mice in the forced-swim test (FST), a behavioral test used to measure the effects of antidepressant agents. Acute administration of 32c (10 mg/kg), or 32d (10 mg/kg) ip tended to decrease the duration of mouse immobility in the FST although the effect was not statistically significant.

Original languageEnglish (US)
Pages (from-to)2047-2068
Number of pages22
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number5
DOIs
Publication statusPublished - Mar 1 2009

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ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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