Design and synthesis of an irreversible dopamine-sparing cocaine antagonist.
Cocaine is a powerful reinforcer and stimulant that binds to specific recognition sites associated with monoamine transporters in the mammalian brain. The search for a functional antagonist to the addictive properties of cocaine has focused on the discovery of a molecule that can inhibit cocaine binding to the dopamine transporter (DAT) but continue to allow dopamine transport by the DAT. No such dopamine-sparing cocaine antagonist has been reported and it is becoming evident that dopamine-sparing antagonism of the pharmacological effects of cocaine by a classical antagonist may not be possible. Herein we present a new concept for the design of dopamine-sparing cocaine antagonists. A unique approach is utilized to deliver an inhibitor that binds irreversibly to the DAT, then cleaves and leaves behind a small fragment attached to the DAT that blocks access by cocaine but permits dopamine transport. The design of these compounds takes advantage of a cysteinyl sulfhydryl group in the DAT. This group is hypothesized to attack the incoming inhibitor and lead to selective inhibition of the cocaine binding site while sparing dopamine transport. This concept of a mechanism based irreversible dopamine-sparing cocaine antagonist has now been demonstrated to be viable and, as example, the unsaturated 6 showed inhibition of cocaine (63%) at the DAT after 24h incubation, while at that point considerably less inhibition of dopamine is manifested (23%). In contrast, the epoxide 7 showed a greater inhibition of dopamine reuptake than cocaine binding at 24h (68% versus 18%).
Meltzer
Peter C
PC
Organix Inc., 240 Salem Street, Woburn, MA 01801, USA. meltzer@organixinc.com
Liu
Shanghao
S
Blanchette
Heather
H
Blundell
Paul
P
Madras
Bertha K
BK
D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003042:Cocaine / Q000037:antagonists & inhibitors*; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000187:drug effects; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D013439:Sulfhydryl Reagents
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007202:Indicators and Reagents; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D013439:Sulfhydryl Reagents; D003042:Cocaine; D004298:Dopamine