Potent substituted-3 beta-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects.
Two novel phenyltropane analogs of cocaine, 3 beta-(4-chlorophenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-31) and 3 beta-(4-methylphenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-32), were evaluated for cocaine-like discriminative stimulus effects in rats. Two groups of rats were trained to discriminate 10 mg/kg cocaine from saline using a standard 2-lever discrimination procedure with correct-lever responding reinforced under a fixed-ratio 20 schedule of food reinforcement. One group of rats was used to evaluate RTI-COC-31 and the unsubstituted-3 beta-phenyltropane reference compound WIN 35,065-2 in substitution tests. Another group of rats was used to evaluate RTI-COC-32. For purposes of comparison, a cocaine dose-effect curve was also determined in each group. Both RTI-COC-31 and RTI-COC-32, as well as WIN 35,065-2, substituted completely for cocaine. RTI-COC-31 was 26.8-fold and RTI-COC-32 was 6-fold more potent than cocaine for producing cocaine-lever responding. The potent cocaine-like effects of the RTI analogs in vivo correspond with their high affinities for a cocaine recognition site on the dopamine transporter, providing further evidence that this site may mediate behavioral effects of cocaine relevant to its abuse.
Balster
R L
RL
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613.
Carroll
F I
FI
Graham
J H
JH
Mansbach
R S
RS
Rahman
M A
MA
Philip
A
A
Lewin
A H
AH
Showalter
V M
VM
D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001245:Association Learning / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects; D013329:Structure-Activity Relationship
D011954:Receptors, Dopamine; C067731:3-(4-chlorophenyl)tropane-2-carboxylic acid methyl ester; C067730:RTI-COC 32; C021278:troparil; D003042:Cocaine