3-Aryl-2-carbomethoxybicyclo[3.2.1]oct-2-enes inhibit WIN 35,428 binding potently and selectively at the dopamine transporter.
The search for medications for cocaine abuse has focused upon the design of potential cocaine antagonists or cocaine substitutes which interact at the dopamine transporter of mammalian systems. This manuscript describes the synthesis and biological evaluation of 8-substituted 2-carbomethoxy-3-arylbicyclo[3.2.1]oct-2-enes. These compounds prove potent and selective inhibitors of the dopamine transporter. Their selectivity results primarily from a reduced inhibitory potency toward the serotonin transporter. This work supports the notion that the orientation of the 3-aryl ring in the bicyclo[3.2.1]octane system affects the interaction of these molecules with the serotonin transporter far more markedly than it affects the interaction with the dopamine transporter.
Meltzer
P C
PC
Organix Inc., Woburn, MA 01801, USA. meltzer@organixinc.com
Blundell
P
P
Huang
H
H
Liu
S
S
Yong
Y F
YF
Madras
B K
BK
D000818:Animals; D001667:Binding, Competitive; D001923:Brain Chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D015283:Citalopram / Q000037:antagonists & inhibitors / 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* / Q000378:metabolism*; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014316:Tritium
D001643:Bridged Bicyclo Compounds; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D014316:Tritium; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine