Synthesis and dopamine receptor binding of sulfur-containing aporphines

Bioorg Med Chem. 2006 Mar 15;14(6):1918-23. doi: 10.1016/j.bmc.2005.10.049. Epub 2005 Nov 15.

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 > or = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aporphines / chemical synthesis*
  • Aporphines / chemistry*
  • Aporphines / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiology
  • Drug Evaluation, Preclinical
  • Male
  • Molecular Structure
  • Motor Activity / drug effects
  • Rats
  • Receptors, Dopamine / metabolism*
  • Sulfur / chemistry*
  • Sulfur / pharmacology

Substances

  • Aporphines
  • Receptors, Dopamine
  • aporphine
  • Sulfur