title: First enantioselective syntheses of the dopamine D1 and D2 receptor modulators, (+)- and (-)-govadine.
abstract: 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.
authors.affiliation: University of British Columbia, Department of Chemistry, Vancouver, BC, Canada.
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhai
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.forename: Glenn
authors.initials: G
authors.lastname: Sammis
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001600:Berberine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D016503:Drug Delivery Systems; D006801:Humans; D015394:Molecular Structure; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D013237:Stereoisomerism
chemical_list: D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C103305:govadine