2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

The Journal of Pharmacology and Experimental Therapeutics
Weimin C HongJ L Katz

Abstract

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3β-aryltropanes with 2β-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2α-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2β-Ph2COCH2-3β-4-Cl-Ph analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2β compounds increased locomotion, only the 2β-(4-ClPh)PhCOCH2-3β-4-Cl-Ph analog had cocaine-like efficacy. None of the 2α-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)- compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in...Continue Reading

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Aug 24, 2011·The Journal of Pharmacology and Experimental Therapeutics·Takato HiranitaJonathan L Katz
Sep 10, 2011·Pharmaceuticals·Jonathan L KatzShang-Yi Tsai
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Feb 13, 2014·The Journal of Pharmacology and Experimental Therapeutics·Takato HiranitaJonathan L Katz
Dec 31, 2014·Drug and Alcohol Dependence·Maarten E A ReithJonathan L Katz

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Citations

Mar 8, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Hai-Ying ZhangZheng-Xiong Xi
Apr 27, 2017·The Journal of Pharmacology and Experimental Therapeutics·Takato HiranitaJonathan L Katz
Jun 28, 2018·The Journal of Pharmacology and Experimental Therapeutics·Weimin C HongJonathan L Katz
Jan 8, 2021·Annual Review of Pharmacology and Toxicology·Amy Hauck NewmanZheng-Xiong Xi
Jun 12, 2019·ACS Chemical Neuroscience·Shaili AggarwalOle V Mortensen

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