Synthesis and dopamine receptor binding of sulfur-containing aporphines.
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.
Tóth
Miklós
M
University of Debrecen, Department of Organic Chemistry, H-4010 PO Box 20, Debrecen, Hungary.
Berényi
Sándor
S
Csutorás
Csaba
C
Kula
Nora S
NS
Zhang
Kehong
K
Baldessarini
Ross J
RJ
Neumeyer
John L
JL
D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D008297:Male; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D013455:Sulfur / Q000737:chemistry* / Q000494:pharmacology
D001060:Aporphines; D011954:Receptors, Dopamine; C081279:aporphine; D013455:Sulfur