First enantioselective syntheses of the dopamine D1 and D2 receptor modulators, (+)- and (−)-govadine

There is a pressing need to find and develop new antipsychotic agents for the treatment of schizophrenia. Current drugs primarily target dopamine D2 receptors and are only effective in the treatment of the positive symptoms of this indication. The tetrahydroprotoberberine natural product (±)-govadin...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1557-1559
Hauptverfasser: Zhai, Huimin, Miller, James, Sammis, Glenn
Format: Artikel
Sprache:eng
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Zusammenfassung:There is a pressing need to find and develop new antipsychotic agents for the treatment of schizophrenia. Current drugs primarily target dopamine D2 receptors and are only effective in the treatment of the positive symptoms of this indication. The tetrahydroprotoberberine natural product (±)-govadine has shown unique promise for the treatment of both the positive and negative symptoms of schizophrenia as it targets both dopamine D1 and D2 receptors. However, further clinical research has been hindered by the lack of availability of significant quantities of enantioenriched material. A new, enantioselective synthetic route has been developed that affords (−)-govadine in 39% overall yield over 5-steps from commercially available dopamine and homovanillic acid derivatives. Using only minor modifications in the synthetic route, (+)-govadine can be synthesized in comparable yields and enantioselectivities. The route is readily scalable as every intermediate was purified by crystallization and no flash column chromatography was necessary.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.01.005