title: 2'-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding.
abstract: Few studies have characterized the effect of substituents at the 2'-position of cocaine on transporter binding potency and selectivity. We synthesized 2'-OH-, 2'-F- and 2'-acetoxy-cocaines and compared their binding potencies for rat dopamine, norepinephrine and 5-hydroxytryptamine transporters to cocaine, 3'-OH-, 4'-OH-, 2'-OH,4'-I-cocaine derivatives, and to the transporter selective ligands WIN 35,428, nisoxetine and paroxetine. Unlike most substitutions, 2'-OH- and 2'-acetoxy-groups increased cocaine's binding potency for the dopamine transporter (10- and 4-fold, respectively). These substituents also enhanced binding to the norepinephrine transporter (52- and 35-fold, respectively) but had less effect on 5-hydroxytryptamine transporter binding. 2'-Hydroxylation also enhanced binding of 4'-I cocaine, an analog with low DA binding potency. The ability of 2'-substituents to substantially increase cocaine binding potency and to alter selectivity for brain transporters indicates the potential importance of the 2'-position in transporter binding.
authors.affiliation: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Seale
authors.forename: K
authors.initials: K
authors.lastname: Avor
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: N
authors.initials: N
authors.lastname: Hall
authors.forename: H M
authors.initials: HM
authors.lastname: Chan
authors.forename: G P
authors.initials: GP
authors.lastname: Basmadjian
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D017374:Paroxetine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine