Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters.
Cocaine interacts with dopamine transporters and sigma receptors at concentrations that are achievable in vivo, suggesting that they may both be viable targets for the development of anti-cocaine agents. Rimcazole binds to both of these targets and also attenuates cocaine-induced locomotor activity and sensitization. To further characterize the mechanism(s) underlying the attenuation of cocaine-induced convulsions and lethality, rimcazole and three analogs (SH3/24, SH2/21, SH1/57), with a range of affinities for dopamine transporters and sigma receptors, were evaluated. The highly selective and potent sigma receptor ligand LR176 was used as a reference. Competition binding studies confirmed that the rank order of the compounds at dopamine transporters vs. sigma receptors differed, thus enabling a correlation between the relative anti-cocaine activities of the compounds in behavioral studies and their affinities for dopamine transporters vs. sigma receptors. In behavioral studies, male Swiss Webster mice were pre-treated with one of the compounds (0-60 mg/kg, i.p.), then challenged 15 min later with either a convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p.) dose of cocaine. When the compounds were ranked according to their protective effect, there was a significant correlation between their anticonvulsant actions and their affinities for sigma receptors, but not dopamine transporters. Although the rimcazole analogs were ineffective against the lethal effects of cocaine, the selective sigma receptor ligand LR176 provided significant protection. These data thus suggest that sigma receptors may mediate some of the toxic effects associated with cocaine and that sigma receptor antagonists may be developed as pharmacotherapeutic agents for this application.
Matsumoto
R R
RR
Dept of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190, USA. rae-matsumoto@ouhsc.edu
Hewett
K L
KL
Pouw
B
B
Bowen
W D
WD
Husbands
S M
SM
Cao
J J
JJ
Newman
A H
AH
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control
D000927:Anticonvulsants; D002227:Carbazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D005021:Ethylamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines; D017480:Receptors, sigma; C085527:BD 1008; C034931:rimcazole; D003042:Cocaine; D004298:Dopamine