2-Isoxazol-3-Phenyltropane derivatives of Cocaine: Molecular and Atypical system effects at the Dopamine Transporter

Takato Hiranita, Derek S. Wilkinson, Weimin C. Hong, Mu Fa Zou, Theresa A. Kopajtic, Paul L. Soto, Carl R. Lupica, Amy H. Newman, Jonathan L. Katz

Research output: Contribution to journalArticlepeer-review

Abstract

The present study examined RTI-371 [3b-(4-methylphenyl)-2b- [3-(4-chlorophenyl)-isoxazol-5-yl]tropane], a phenyltropane cocaine analog with effects distinct from cocaine, and assessed potential mechanisms for those effects by comparison with its constitutional isomer, RTI-336 [3b-(4-chlorophenyl)-2b-[3-(4- methylphenyl)-isoxazol-5-yl]tropane]. In mice, RTI-371 was less effective than cocaine and RTI-336 in stimulating locomotion, and incompletely substituted (~60%maximum at 5 minutes or 1 hour after injection) in a cocaine (10 mg/kg i.p.)/saline discrimination procedure; RTI-336 completely substituted. In contrast to RTI- 336, RTI-371 was not self-Administered, and its pretreatment (1.0-10 mg/kg i.p.) dose-dependently decreased maximal cocaine self-Administration more potently than food-maintained responding. RTI-336 pretreatment dose-dependently left-shifted the cocaine self-Administration dose-effect curve. Both RTI-336 and RTI-371 displaced [3H]WIN35,428 [[3H](2)-3b-(4-fluorophenyl)- tropan-2b-carboxylic acid methyl ester tartrate] binding to striatal dopamine transporters (DATs) with Ki values of 10.8 and 7.81 nM, respectively, and had lower affinities at serotonin or norepinephrine transporters, or muscarinic and s receptors. The relative low affinity at these sites suggests the DAT as the primary target of RTI-371 with minimal contributions from these other targets. In biochemical assays probing the outward-facing DAT conformation, both RTI-371 and RTI-336 had effects similar to cocaine, suggesting little contribution of DAT conformation to the unique pharmacology of RTI-371. The locomotor-stimulant effects of RTI-371 (3.0-30 mg/kg i.p.) were comparable in wildtype and knockout cannabinoid CB1 receptor (CB1R) mice, indicating that previously reported CB1 allosteric effects do not decrease cocaine-like effects of RTI-371. DAT occupancy in vivo was most rapid with cocaine and least with RTI-371. The slow apparent association rate may allow compensatory actions that in turn dampen cocaine-like stimulation, and give RTI-371 its unique pharmacologic profile.

Original languageEnglish (US)
Pages (from-to)297-309
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume349
Issue number2
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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