title: 2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations.
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 affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2β- and 2α-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine.
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Weimin C
authors.initials: WC
authors.lastname: Hong
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kopajtic
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Lomenzo
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Bernandie
authors.initials: B
authors.lastname: Jean
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Madura
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Surratt
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Trudell
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Psychobiology Section (T.A.K., J.L.K.), Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Chemistry Department (L.X., S.A.L., M.L.T.), University of New Orleans, New Orleans, Louisiana; Department of Chemistry and Biochemistry (B.J., J.D.M.) and Division of Pharmaceutical Sciences (C.K.S.), Duquesne University, Pittsburgh, Pennsylvania jkatz@intra.nida.nih.gov.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
mesh_terms: D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D003042:Cocaine