Synthesis of 3-carbamoylecgonine methyl ester analogues as inhibitors of cocaine binding and dopamine uptake.
Five (1R-2-exo-3-exo)-3-(N-phenylcarbamoyl)ecgonine methyl ester analogues were synthesized and characterized by 1H and 13C NMR, IR, and thermospray MS. The compounds were synthesized in two or three steps as (-)-stereoisomers from (-)-ecgonine in good yield (56% overall). These cocaine derivatives were assessed for their ability to inhibit [3H]cocaine binding to rat striatal tissue and to inhibit [3H]dopamine uptake into synaptosomes prepared from the same tissue. The most potent of the analogues was (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo[3.2.1]octyl 3-N-(3'-nitrophenyl)carbamate. IC50 values for inhibition of cocaine binding and dopamine uptake were 37 and 178 nM, respectively. Amino derivatives were less active than the nitro and (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo [3.2.1]octyl 3-N-(4'-aminophenyl)carbamate had the lowest affinity for the receptor with IC50 values of 63 and greater than 100 microM in the aforementioned assays, respectively.
Kline
R H
RH
Department of Biomedicinal Chemistry, University of Maryland, Baltimore 21201.
Wright
J
J
Eshleman
A J
AJ
Fox
K M
KM
Eldefrawi
M E
ME
D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins; D055598:Chemical Phenomena; D002621:Chemistry; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D011955:Receptors, Drug; C061445:cocaine receptor; D003042:Cocaine; D004298:Dopamine; C034524:ecgonine methyl ester