2'-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies.
A series of 2'-substituted cocaine analogs (4-8) was prepared and evaluated in an in vitro dopamine transporter (DAT) binding assay. Compounds 4-7 were prepared by esterifying the 3 beta-hydroxyl group of ecgonine methyl ester (3) using the appropriate acid chloride in the presence of Et3N and benzene. Compound 3 was obtained from cocaine (1) by hydrolysis using 1N HCl to afford ecgonine.HCl which was subjected to acid catalyzed esterification using methanol saturated with HCl gas. Compound 8 was obtained by hydrogenation of 7 using H2/Pd-C. The IC50 values were calculated from displacement experiment of the radioligand [3H]WIN-35,428 (2). 2'-Aminococaine (8) showed high binding affinity to the DAT (14- and 1.3-fold more active than cocaine and the radioligand 2, respectively). These results, along with previous results, emphasize the importance of a hydrogen-bond donor group at the 2'-position of cocaine to enhance binding affinity to the DAT.
el-Moselhy
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Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. mona63@hotmail.com
Avor
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Basmadjian
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D000818:Animals; D001921:Brain / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine