Alkylation of rat dopamine transporters and blockade of dopamine uptake by EEDQ.
Effects of the alkylating agent EEDQ (N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline) on levels of dopamine transporter (DA(T)) and function were examined in caudate-putamen (CPu) tissue from rat brain. EEDQ produced profound, dose-dependent decreases in DA(T) binding in homogenates (IC(50)=78 microM) and frozen sections (IC(75)=200 microM) that were not reversed by washing. EEDQ also blocked uptake of [(3)H]DA in CPu synaptosomes (IC(50)=17 microM). However, single (10 mg/kg) or repeated administration of EEDQ in vivo (15 mg/kg/day x 3) did not alter DA(T) levels or DA uptake in CPu. Pretreatment of rats with alpha-methyl-p-tyrosine and reserpine to deplete endogenous dopamine also failed to lower DA(T) levels in CPu after injections of EEDQ. EEDQ is an effective alkylating agent for DA(T) in vitro, but not to evaluate metabolic turnover or function of DA(T) in vivo. The results encourage development of selective and in vivo-active DA(T)-alkylating agents.
Tarazi
F I
FI
Mailman Research Center, McLean Division of Massachusetts General Hospital, 115 Mill Street, Belmont, MA 02748, USA. ftarazi@hms.harvard.edu
Kula
N S
NS
Zhang
K
K
Baldessarini
R J
RJ
D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects*; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000477:Alkylating Agents; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011804:Quinolines; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; C000470:EEDQ; D003042:Cocaine; D004298:Dopamine