Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine.
There is a large unmet medical need for cocaine addiction treatments. Studies have indicated that the dopamine transporter (DAT) is the primary biological target of cocaine, and most drugs that have DAT affinity have behavioral effects like those of cocaine. However, analogs of benztropine have high DAT affinity and behavioral effects that show varying degrees of similarity to cocaine. We now report the discovery that a benztropine analog, JHW007, with high affinity for the DAT does not have cocaine-like behavioral effects and antagonizes the effects of cocaine. JHW007 occupied the DAT in vivo more slowly than did cocaine and had not reached an apparent plateau up to 270 min after injection. The in vivo binding of cocaine to the DAT suggested rate of DAT occupancy as an important contributor to its behavioral effects, and the slow association with the DAT may provide an explanation for JHW007 being relatively devoid of cocaine-like behavioral effects. The antagonism of cocaine suggests that DAT ligands with reduced cocaine-like activity can function as cocaine antagonists and suggests JHW007 as a lead for discovery of cocaine-abuse pharmacotherapeutics.
Desai
Rajeev I
RI
Psychobiology, Medications Discovery Research Branch, National Institute on Drug Abuse, Intramural Research Program, Department of Health and Human Services, National Institutes of Health, Baltimore, Maryland 21224, USA.
Kopajtic
Theresa A
TA
Koffarnus
Mikhail
M
Newman
Amy Hauck
AH
Katz
Jonathan L
JL
D000818:Animals; D001590:Benztropine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects*; D026901:Membrane Transport Proteins / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D051381:Rats
D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C504726:N-(n-butyl)-(bis-fluorophenyl)methoxytropane; C504727:N-allyl-(bisfluorophenyl)methoxytropane; D009419:Nerve Tissue Proteins; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; C079213:RTI 121; D001590:Benztropine; D003042:Cocaine
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