TY - JOUR
T1 - 2-Isoxazol-3-Phenyltropane derivatives of Cocaine
T2 - Molecular and Atypical system effects at the Dopamine Transporter
AU - Hiranita, Takato
AU - Wilkinson, Derek S.
AU - Hong, Weimin C.
AU - Zou, Mu Fa
AU - Kopajtic, Theresa A.
AU - Soto, Paul L.
AU - Lupica, Carl R.
AU - Newman, Amy H.
AU - Katz, Jonathan L.
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.113.212738
DO - 10.1124/jpet.113.212738
M3 - Article
C2 - 24518035
AN - SCOPUS:84898008454
SN - 0022-3565
VL - 349
SP - 297
EP - 309
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -