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

doi:10.1016/j.bmcl.2010.11.076

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

Psychiatry

Research output: Contribution to journal › Article › peer-review

5 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 language	English (US)
Pages (from-to)	48-51
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2010.11.076
State	Published - Jan 1 2011

Funding

This work was supported by the National Institute on Drug Abuse (P.C.M.: DA11542 ; A.J.: DAO18165 ; B.K.M.: DA06303 ) and by the VA Merit Review and Research Career Scientist Programs (A.J.).

Funders	Funder number
VA Merit Review and Research Career Scientist Programs
National Institute on Drug Abuse	DA06303, R01DA011542, DAO18165

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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10.1016/j.bmcl.2010.11.076

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

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.",

keywords = "Cocaine medications, Dopamine Transporter, Monoamine transporter ligands, Tropanes",

author = "Madhusudhan Purushotham and Anjaneyulu Sheri and Pham-Huu, \{Duy Phong\} and Madras, \{Bertha K.\} and Aaron Janowsky and Meltzer, \{Peter C.\}",

note = "Funding Information: This work was supported by the National Institute on Drug Abuse (P.C.M.: DA11542 ; A.J.: DAO18165 ; B.K.M.: DA06303 ) and by the VA Merit Review and Research Career Scientist Programs (A.J.). ",

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AU - Pham-Huu, Duy Phong

AU - Madras, Bertha K.

AU - Janowsky, Aaron

AU - Meltzer, Peter C.

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N2 - 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.

AB - 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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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