Synthesis and dopamine receptor binding of sulfur-containing aporphines

Miklós Tóth, Sándor Berényi, Csaba Csutorás, Nora S. Kula, Kehong Zhang, Ross J. Baldessarini, John L. Neumeyer

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21 Citations (Scopus)

Abstract

We investigated acid-catalyzed rearrangement of thebaine 14 and its N-propyl analog 15 with methanesulfonic acid in the presence of the nucleophiles methanethiol and hydrogen sulfide. R(-)-2-methylthioapocodeine 16, R(-)-2-methylthioapomorphine 18, and their N-n-propyl analogs 17, 19 were obtained by rearrangement in the presence of methanethiol. However, with hydrogen sulfide, rearrangement of thebaine 14 and its N-n-propyl analog 15 produced sulfide-linked bis-aporphines 21-24 instead of expected R(-)-2-mercaptoapocodeines 12, 13 and R(-)-2-mercaptoapomorphines 10, 11. R(-)-2-Methylthio-N-n-propylnorapomorphine 19 had higher affinity (Ki = 3.7 nM) at D2 receptors in rat forebrain tissue than other novel 2-substituted sulfur-containing aporphines (Ki ≥ 50 nM). Behavioral testing of the novel agents in rat indicated moderate locomotor arousal after systemic injection, and none after intragastric administration, indicating poor oral bioavailability.

Original languageEnglish
Pages (from-to)1918-1923
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number6
DOIs
Publication statusPublished - Mar 15 2006

Keywords

  • Apomorphine
  • Aporphine derivatives
  • D receptors
  • Dopamine agonists

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Tóth, M., Berényi, S., Csutorás, C., Kula, N. S., Zhang, K., Baldessarini, R. J., & Neumeyer, J. L. (2006). Synthesis and dopamine receptor binding of sulfur-containing aporphines. Bioorganic and Medicinal Chemistry, 14(6), 1918-1923. https://doi.org/10.1016/j.bmc.2005.10.049