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 Citations (Scopus)

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

Fingerprint

Octanes
Dopamine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Cocaine
Central Nervous System Stimulants
Isoxazoles
Drug therapy
Cocaine-Related Disorders
Aptitude
Inhibitory Concentration 50
Neurons
Drug Therapy

Keywords

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

ASJC Scopus subject areas

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

Cite this

The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes. / Purushotham, Madhusudhan; Sheri, Anjaneyulu; Pham-Huu, Duy Phong; Madras, Bertha K.; Janowsky, Aaron; Meltzer, Peter C.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 1, 01.01.2011, p. 48-51.

Research output: Contribution to journalArticle

Purushotham, Madhusudhan ; Sheri, Anjaneyulu ; Pham-Huu, Duy Phong ; Madras, Bertha K. ; Janowsky, Aaron ; Meltzer, Peter C. / The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 1. pp. 48-51.
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