Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter.
Several potentially irreversible ligands (i.e., wash-resistant binding inhibitors) for the cocaine receptor site on the dopamine transporter, derived from (-)-cocaine or 3 beta-phenyltropan-2 beta-carboxylic acid methyl ester (WIN 35,065-2), were prepared and shown to produce wash-resistant inhibition of [3H]-3 beta-(p-fluorophenyl)tropan-2 beta-carboxylic acid methyl ester ([3H]WIN 35,428) binding. All the compounds prepared had the same absolute configuration as cocaine; they include analogues possessing chemically reactive groups such as the isothiocyanato and bromoacetamido as well as photoactive azido groups. The potentially irreversible ligands, as well as all the intermediates prepared in this study, were evaluated for their ability to inhibit the binding of [3H]WIN 35,428 in coincubation experiments. Of the potentially irreversible ligands, 3 beta-(p-chlorophenyl)tropan-2 beta-carboxylic acid 2-[p-(bromoacetamido)phenyl]ethyl ester (6c) had the highest apparent potency. The potentially irreversible ligands were also preincubated, and inhibition of [3H]WIN 35,428 binding was determined both before and after washing the ligand-exposed tissues. The most effective ligands in this regard were 3 beta-(3-iodo-4-azidophenyl)tropan-2 beta-carboxylic acid methyl ester (5) and 3 beta-(p-chlorophenyl)tropan-2 beta-carboxylic acid 2-(3-iodo-4-azidophenyl)ethyl ester (6d). The structure-activity relationships of these data are discussed.
Carroll
F I
FI
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709.
Gao
Y
Y
Abraham
P
P
Lewin
A H
AH
Lew
R
R
Patel
A
A
Boja
J W
JW
Kuhar
M J
MJ
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000737:chemistry*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D011955:Receptors, Drug; C061445:cocaine receptor; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C021278:troparil; D003042:Cocaine