University of British Columbia, Department of Chemistry, Vancouver, BC, Canada.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1557-9. doi: 10.1016/j.bmcl.2012.01.005. Epub 2012 Jan 10.
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.
目前迫切需要寻找和开发新的抗精神病药物来治疗精神分裂症。目前的药物主要针对多巴胺 D2 受体，仅对该适应症的阳性症状有效。四氢原小檗碱天然产物（±）-govadine 具有治疗精神分裂症阳性和阴性症状的独特潜力，因为它同时针对多巴胺 D1 和 D2 受体。然而，由于缺乏大量对映体富集物质，进一步的临床研究受到阻碍。已经开发出一种新的对映选择性合成路线，从商业上可获得的多巴胺和高香草酸衍生物出发，以 5 步总收率 39%得到（-）-govadine。通过对合成路线进行微小修改，（+）-govadine 可以以类似的收率和对映选择性合成。该路线易于扩展，因为每个中间体都通过结晶纯化，不需要快速柱层析。
