Synthesis of 8-thiabicyclo[3.2.1]oct-2-enes and their binding affinity for the dopamine and serotonin transporters.
The reinforcing and stimulant properties of cocaine have been primarily associated with its propensity to bind to monoamine transport systems, in particular the dopamine transporter. Inhibition of the dopamine transporter then leads to an increase of synaptic dopamine with substantial pharmacological consequences. The search for medications for cocaine abuse has had a particular focus on tropane analogs of cocaine, and the interchange of nitrogen for oxygen in this class has led to potent and selective inhibitors of monoamine transport. Herein we report that 8-thiatrop-2-enes are highly potent and quite selective inhibitors of the dopamine transporter. The 3,4-dichlorophenyl-8-thiabicyclo[3.2.1]oct-2-ene (4f) is particularly potent (IC50=4.5 nM) and selective (800-fold) with respect to inhibition of the serotonin transporter.
Meltzer
Peter C
PC
Organix Inc., 240 Salem Street, Woburn, MA 01801, USA. meltzer@organix.inc.com
Pham-Huu
Duy-Phong
DP
Madras
Bertha K
BK
D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship
D000475:Alkenes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine