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Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs with Atypical Behavioral Effects.
J Pharmacol Exp Ther. 2018 09; 366(3):527-540.JP

Abstract

Atypical dopamine transporter (DAT) inhibitors, despite high DAT affinity, do not produce the psychomotor stimulant and abuse profile of standard DAT inhibitors such as cocaine. Proposed contributing features for those differences include off-target actions, slow onsets of action, and ligand bias regarding DAT conformation. Several 3α-(4',4''-difluoro-diphenylmethoxy)tropanes were examined, including those with the following substitutions: N-(indole-3''-ethyl)- (GA1-69), N-(R)-2''-amino-3''-methyl-n-butyl- (GA2-50), N-2''aminoethyl- (GA2-99), and N-(cyclopropylmethyl)- (JHW013). These compounds were previously reported to have rapid onset of behavioral effects and were presently evaluated pharmacologically alone or in combination with cocaine. DAT conformational mode was assessed by substituted-cysteine accessibility and molecular dynamics (MD) simulations. As determined by substituted-cysteine alkylation, all BZT analogs except GA2-99 showed bias for a cytoplasmic-facing DAT conformation, whereas cocaine stabilized the extracellular-facing conformation. MD simulations suggested that several analog-DAT complexes formed stable R85-D476 "outer gate" bonds that close the DAT to extracellular space. GA2-99 diverged from this pattern, yet had effects similar to those of other atypical DAT inhibitors. Apparent DAT association rates of the BZT analogs in vivo were slower than that for cocaine. None of the compounds was self-administered or stimulated locomotion, and each blocked those effects of cocaine. The present findings provide more detail on ligand-induced DAT conformations and indicate that aspects of DAT conformation other than "open" versus "closed" may facilitate predictions of the actions of DAT inhibitors and may promote rational design of potential treatments for psychomotor-stimulant abuse.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.).Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana (W.C.H.); Division of Pharmaceutical Sciences (M.J.W., C.K.S.) and Department of Chemistry and Biochemistry (J.D.M.), Duquesne University, Pittsburgh; and Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (D.S.W., T.H., L.L., S.H., D.B.S., J.L.K.) jkatzzz@gmail.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29945932

Citation

Hong, Weimin C., et al. "Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs With Atypical Behavioral Effects." The Journal of Pharmacology and Experimental Therapeutics, vol. 366, no. 3, 2018, pp. 527-540.
Hong WC, Wasko MJ, Wilkinson DS, et al. Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs with Atypical Behavioral Effects. J Pharmacol Exp Ther. 2018;366(3):527-540.
Hong, W. C., Wasko, M. J., Wilkinson, D. S., Hiranita, T., Li, L., Hayashi, S., Snell, D. B., Madura, J. D., Surratt, C. K., & Katz, J. L. (2018). Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs with Atypical Behavioral Effects. The Journal of Pharmacology and Experimental Therapeutics, 366(3), 527-540. https://doi.org/10.1124/jpet.118.250498
Hong WC, et al. Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs With Atypical Behavioral Effects. J Pharmacol Exp Ther. 2018;366(3):527-540. PubMed PMID: 29945932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs with Atypical Behavioral Effects. AU - Hong,Weimin C, AU - Wasko,Michael J, AU - Wilkinson,Derek S, AU - Hiranita,Takato, AU - Li,Libin, AU - Hayashi,Shuichiro, AU - Snell,David B, AU - Madura,Jeffry D, AU - Surratt,Christopher K, AU - Katz,Jonathan L, Y1 - 2018/06/26/ PY - 2018/05/08/received PY - 2018/06/22/accepted PY - 2018/6/28/pubmed PY - 2019/7/30/medline PY - 2018/6/28/entrez SP - 527 EP - 540 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 366 IS - 3 N2 - Atypical dopamine transporter (DAT) inhibitors, despite high DAT affinity, do not produce the psychomotor stimulant and abuse profile of standard DAT inhibitors such as cocaine. Proposed contributing features for those differences include off-target actions, slow onsets of action, and ligand bias regarding DAT conformation. Several 3α-(4',4''-difluoro-diphenylmethoxy)tropanes were examined, including those with the following substitutions: N-(indole-3''-ethyl)- (GA1-69), N-(R)-2''-amino-3''-methyl-n-butyl- (GA2-50), N-2''aminoethyl- (GA2-99), and N-(cyclopropylmethyl)- (JHW013). These compounds were previously reported to have rapid onset of behavioral effects and were presently evaluated pharmacologically alone or in combination with cocaine. DAT conformational mode was assessed by substituted-cysteine accessibility and molecular dynamics (MD) simulations. As determined by substituted-cysteine alkylation, all BZT analogs except GA2-99 showed bias for a cytoplasmic-facing DAT conformation, whereas cocaine stabilized the extracellular-facing conformation. MD simulations suggested that several analog-DAT complexes formed stable R85-D476 "outer gate" bonds that close the DAT to extracellular space. GA2-99 diverged from this pattern, yet had effects similar to those of other atypical DAT inhibitors. Apparent DAT association rates of the BZT analogs in vivo were slower than that for cocaine. None of the compounds was self-administered or stimulated locomotion, and each blocked those effects of cocaine. The present findings provide more detail on ligand-induced DAT conformations and indicate that aspects of DAT conformation other than "open" versus "closed" may facilitate predictions of the actions of DAT inhibitors and may promote rational design of potential treatments for psychomotor-stimulant abuse. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/29945932/Dopamine_Transporter_Dynamics_of_N-Substituted_Benztropine_Analogs_with_Atypical_Behavioral_Effects L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=29945932 DB - PRIME DP - Unbound Medicine ER -