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

The 2-(3-methylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes are potent and selective inhibitors of the Dopamine Transporter (DAT). Isoxazoles 6c (3β-(4-fluorophenyl)) and 6d (3β-(4-chlorophenyl)) inhibit the DAT (IC50=7nM) and are inactive at Serotonin Transporter inhibition (IC50 >1000nM)....

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-01, Vol.21 (1), p.48-51
Main Authors: Purushotham, Madhusudhan, Sheri, Anjaneyulu, Pham-Huu, Duy-Phong, Madras, Bertha K., Janowsky, Aaron, Meltzer, Peter C.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
central nervous system
chemistry
cocaine
Cocaine medications
dopamine
Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors
Dopamine Plasma Membrane Transport Proteins - metabolism
Dopamine Transporter
Dopamine Uptake Inhibitors - chemical synthesis
Dopamine Uptake Inhibitors - chemistry
Dopamine Uptake Inhibitors - pharmacology
Humans
Isoxazoles - chemistry
Medical sciences
Miscellaneous
Monoamine transporter ligands
neurons
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
octanes
Pharmacology. Drug treatments
Protein Binding
Selective Serotonin Reuptake Inhibitors - chemical synthesis
Selective Serotonin Reuptake Inhibitors - chemistry
Selective Serotonin Reuptake Inhibitors - pharmacology
serotonin
Serotonin Plasma Membrane Transport Proteins - chemistry
Serotonin Plasma Membrane Transport Proteins - metabolism
Tropanes
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Summary:The 2-(3-methylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes are potent and selective inhibitors of the Dopamine Transporter (DAT). Isoxazoles 6c (3β-(4-fluorophenyl)) and 6d (3β-(4-chlorophenyl)) inhibit the DAT (IC50=7nM) and are inactive at Serotonin Transporter inhibition (IC50 >1000nM). 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=7–43nM) with substantial selectivity versus inhibition of SERT.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.11.076