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 Citations (Scopus)

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
StatePublished - Mar 1 2009

Fingerprint

Furans
Serotonin Uptake Inhibitors
Serotonin
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Aptitude
Bearings (structural)
Cocaine
Synaptic Transmission
Lead compounds
Antidepressive Agents
Inhibitory Concentration 50
Amines
Dissection
Neurotransmitter Agents
Stereochemistry
Dopamine
Norepinephrine
Depression

ASJC Scopus subject areas

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

Cite this

2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors. / Voelker, Troy; Xia, Haiji; Fandrick, Keith; Johnson, Robert; Janowsky, Aaron; Cashman, John R.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 5, 01.03.2009, p. 2047-2068.

Research output: Contribution to journalArticle

Voelker, Troy ; Xia, Haiji ; Fandrick, Keith ; Johnson, Robert ; Janowsky, Aaron ; Cashman, John R. / 2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 5. pp. 2047-2068.
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