Synthesis and dopamine receptor binding of sulfur-containing aporphines

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 ( K i  = 3.7 nM) at D 2 receptors in rat forebrain tissue than other novel 2-substituted sulfur-containing aporphines ( K i  ⩾ 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.