Highly potent cocaine analogs cause long-lasting increases in locomotor activity.
Three cocaine analogs were compared with cocaine for the capacity to affect: (1) dopamine transporter binding and function; and (2) locomotor activity. RTI-55 (3 beta-[4-iodophenyl]tropane-2 beta-carboxylic acid methyl ester tartrate), RTI-121 (3 beta-[4-iodophenyl] tropan-2 beta-carboxylic acid isopropyl ester hydrochloride) and RTI-130 (3 beta-[4-chlorophenyl-2 beta-[1,2,4-oxadiazol-3-phenyl-5-yl]tropane hydrochloride) competed for [3H]WIN 35428 binding in rat striatum in vitro, with IC50 values at least 50-fold less than that of cocaine. These analogs inhibited [3H]dopamine transport into rat striatal synaptosomes, with IC50 values again less (at least 100-fold) than that for cocaine. Intravenous RTI-55, RTI-121 or RTI-130 injection effected dose-related increases in locomotor activity in mice, with estimated relative potencies at least 10-fold greater than that of cocaine. These increases were long lasting: whereas increased activity ceased within 2 h after cocaine administration, increased locomotion was observed at least 10 h after RTI-55, RTI-121, or RTI-130 administration. Parallel line analysis indicated that the slopes of the ascending portion of the RTI-121 and RTI-130 dose-response curves differed from that of cocaine, suggesting the involvement of mechanisms different from that of cocaine.
National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
A E
AE
Fleckenstein
T A
TA
Kopajtic
J W
JW
Boja
F I
FI
Carroll
M J
MJ
Kuhar
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; C103519:RTI 130; C079213:RTI 121; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine