The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes

Madhusudhan Purushotham, Anjaneyulu Sheri, Duy Phong Pham-Huu, Bertha K. Madras, Aaron Janowsky, Peter C. Meltzer

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Cocaine, a potent stimulant of the central nervous system, owes its reinforcing and stimulant properties to its ability to inhibit monoamine uptake systems such as the Dopamine Transporter (DAT), and the Serotonin Transporter (SERT) located on presynaptic neurons in the striatum. The search for pharmacotherapies for cocaine addiction has focused on the design of compounds that bind selectively to the DAT and manifest slow onset of stimulatory action with long duration of action. We had reported that 3-aryl-2-carbomethoxy-8- thiabicyclo[3.2.1]octanes are potent and selective inhibitors of the DAT. In this Letter we report on the effects of replacement of the 2-carbomethoy group by a 2-isoxazole. This new class of 8-thiabicyclo[3.2.1]octanes provides potent and selective inhibitors of the DAT. The 3β-aryl compounds are particularly potent inhibitors of DAT (IC50 = 7-43 nM) with substantial selectivity versus inhibition of SERT.

Original languageEnglish (US)
Pages (from-to)48-51
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • Cocaine medications
  • Dopamine Transporter
  • Monoamine transporter ligands
  • Tropanes

ASJC Scopus subject areas

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

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