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2‐Substituted Aryltropane Cocaine Analogs Produce Atypical DAT Inhibitor Effects without Inducing Inward‐Facing DAT Conformations
Author(s) -
Hong Weimin,
Kopajtic Theresa,
Xu Lifen,
Lomenzo Stacey,
Trudell Mark,
Katz Jonathan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.930.7
Subject(s) - chemistry , dopamine transporter , pharmacology , stereochemistry , dopamine , enantiomer , benztropine , transporter , biochemistry , psychology , neuroscience , medicine , gene
Previous structure‐activity studies indicated that a series of cocaine analogs (3ß‐aryltropanes with various 2ß‐diarylmethoxy substitutions) selectively bind the dopamine transporter (DAT) with nM affinity, and with corresponding 2α‐enantiomers having 10‐fold lower affinity. The present study assessed the similarity to cocaine of behavioral effects of several of these compounds by examining effects on locomotion in mice and substitution for cocaine (10 mg/kg, ip) in rats discriminating cocaine from saline. Despite DAT affinity only the 2β‐Ph 2 COCH 2 ‐3ß‐4‐Cl‐Ph analog fully substituted for cocaine's discriminative effects. Whereas all of the 2β compounds increased locomotion, only the 2β‐(4‐ClPh)PhCOCH 2 ‐3ß‐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, effects of the analogs on DAT conformation were assessed using a cysteine‐accessibility assay. Previous results suggest that cocaine induces an outward‐facing DAT conformation, whereas atypical DAT‐inhibitors, such as benztropine, produce behavioral effects distinct from those of cocaine presumably by inducing an inward‐facing conformation. Most of the 2β‐ and 2α‐substituted compounds induced an outward‐facing DAT conformation similar to that induced by cocaine. Consistent with a previous study of phenyltropane analogs, these behavioral and biochemical results show that phenyltropane analogs can bind to the DAT and induce outward‐facing DAT conformations like cocaine and still produce effects that differ from those of cocaine.