Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice.
Previous studies have shown that BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and related analogs attenuate the toxicity and stimulant effects of cocaine through antagonism of sigma receptors. In the present study, six analogs of BD1008 (UMB 98-103) were synthesized and evaluated in receptor binding and behavioral studies. Competition binding studies confirmed that all six compounds have high affinity for sigma1 receptors, moderate affinity for sigma2 receptors, and low to negligible affinity for monoamine transporters, opioid, N-methyl-D-aspartate, dopamine, and 5-HT receptors. In behavioral pharmacological studies, pretreatment of mice with UMB 100, UMB 101, or UMB 103 significantly attenuated cocaine-induced convulsions and lethality. Together with earlier studies, the data suggest that analogs of BD1008 are promising medication development leads for reducing the toxicity of cocaine.
Matsumoto
Rae R
RR
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, P.O. Box 26901, CPB 337 Oklahoma City, OK 73190, USA. rae_matsumoto@ouhsc.edu
Gilmore
Deborah L
DL
Pouw
Buddy
B
Bowen
Wayne D
WD
Williams
Wanda
W
Kausar
Amina
A
Coop
Andrew
A
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005021:Ethylamines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011759:Pyrrolidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*
D005021:Ethylamines; D008024:Ligands; D011759:Pyrrolidines; D017480:Receptors, sigma; C085527:BD 1008; D003042:Cocaine