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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Purushotham, Madhusudhan¹  Sheri, Anjaneyulu¹  Pham-Huu, Duy-Phong¹  Madras, Bertha K.^4,5  Janowsky, Aaron^2,3  Meltzer, Peter C.¹ 

[1] Organix Inc, Woburn, MA 01801 USA

[2] VA Med Ctr, Portland, OR 97239 USA

[3] Oregon Hlth & Sci Univ, Portland, OR 97239 USA

[4] Harvard Univ, Sch Med, Southborough, MA 01772 USA

[5] New England Reg Primate Res Ctr, Southborough, MA 01772 USA

关键词: Tropanes;    Dopamine Transporter;    Monoamine transporter ligands;    Cocaine medications;   

DOI  :  10.1016/j.bmcl.2010.11.076

来源: Elsevier

【 摘 要 】

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 3 beta-aryl compounds are particularly potent inhibitors of DAT (IC50 = 7-43 nM) with substantial selectivity versus inhibition of SERT. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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