Studies of the Biogenic Amine Transporters. 13. Identification of Agonist and Antagonist Allosteric Modulators of Amphetamine-Induced Dopamine Release

Recent studies identified novel allosteric modulators of the dopamine (DA) transporter (DAT). N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine (SoRI-9804), N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine (SoRI-20040), and N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine (SoRI-20041) partially inhibited [I-125]3 beta-(4'-iodophenyl)tropan-2 beta-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of [I-125]RTI-55 from the DAT, and partially inhibited [H-3] dopamine uptake. In the present study, we report that SoRI-9804 and SoRI-20040, at doses that do not alter release, partially inhibited D-amphetamine-induced DAT-mediated release of [H-3]1-methyl-4-phenylpyridinium (MPP+) or [H-3]dopamine from striatal synaptosomes (DAT-mediated DA release) in a dose-dependent manner. SoRI-20041, which does not alter DAT-mediated DA release measured with [H-3]DA, reversed the effect of SoRI-20040. SoRI-20040 and SoRI-9804 also partially inhibited DAT-mediated DA release induced by DA or (+/-)-3,4-methylenedioxyamphetamine, demonstrating that the observed partial inhibition is not specific for a particular DAT substrate. SoRI-9804 and SoRI-20040 did not attenuate D-amphetamine-induced release of [H-3]5-hydroxytryptamine from serotonergic, or [H-3]MPP+ from noradrenergic, nerve terminals. Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed D-amphetamine-induced release of [H-3]MPP+ from dopaminergic nerve terminals without altering the apparent rate constants. The two major findings of this study are 1) the identification of both agonist (SoRI-9804 and SoRI-20040) and antagonist (SoRI-20041) allosteric modulators of D-amphetamine-induced DAT-mediated DA release and 2) [H-3]DA uptake and D-amphetamine-induced DAT-mediated efflux can be separately modulated. Such agents may have therapeutic potential for the treatment of stimulant addiction, Parkinson's disease, and other psychiatric disorders.