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

Q3 · MEDICINE

Article

Author: Dersch, Christina M. ; Ananthan, Subramaniam ; Rothman, Richard B. ; Partilla, John S.

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 [(125)I]3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of [(125)I]RTI-55 from the DAT, and partially inhibited [(3)H]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 [(3)H]1-methyl-4-phenylpyridinium (MPP(+))or[(3)H]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 [(3)H]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 [(3)H]5-hydroxytryptamine from serotonergic, or [(3)H]MPP(+) from noradrenergic, nerve terminals. Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed D-amphetamine-induced release of [(3)H]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) [(3)H]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.

01 Jul 2008·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Studies of the Biogenic Amine Transporters. 12. Identification of Novel Partial Inhibitors of Amphetamine-Induced Dopamine Release

Q3 · MEDICINE

Article

Author: Joseph J. Pariser ; Richard B. Rothman ; John S. Partilla ; Christina M. Dersch ; Subramaniam Ananthan

Previous studies identified partial inhibitors and allosteric modulators of 5-hydroxytryptamine ([5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamic acid ethyl ester [SoRI-6238], 4-(2-[bis(4-fluorophenyl)methoxy]ethyl)-1-(2-trifluoromethyl-benzyl)-piperidine [TB-1-099]) and dopamine transporters N-(diphenylmethyl)-2-phenyl-4-quinazolinamine, [SoRI-9804]). We report here the identification of three novel allosteric modulators of the dopamine transporter [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine [SoRI-20040], N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine [SoRI-20041], and [4-amino-6-[(diphenylmethyl)amino]-5-nitro-2-pyridinyl]carbamic acid ethyl ester [SoRI-2827]]. Membranes were prepared from human embryonic kidney cells expressing the cloned human dopamine transporter (hDAT). [(125)I]3beta-(4'-Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures. SoRI-20040, SoRI-20041, and SoRI-2827 partially inhibited [(125)I]RTI-55 binding, with EC(50) values ranging from approximately 1.4 to 3 microM and E(max) values decreasing as the [(125)I]RTI-55 concentrations increased. All three compounds decreased the [(125)I]RTI-55 B(max) value and increased the apparent K(d) value in a manner well described by a sigmoid dose-response curve. In dissociation rate experiments, SoRI-20040 (10 microM) and SoRI-20041 (10 microM), but not SoRI-2827 (10 microM), slowed the dissociation of [(125)I]RTI-55 from hDAT by approximately 30%. Using rat brain synaptosomes, all three agents partially inhibited [(3)H]dopamine uptake, with EC(50) values ranging from 1.8 to 3.1 microM and decreased the V(max) value in a dose-dependent manner. SoRI-9804 and SoRI-20040 partially inhibited amphetamine-induced dopamine transporter-mediated release of [(3)H]1-methyl-4-phenylpyridinium ion from rat caudate synaptosomes in a dose-dependent manner. Viewed collectively, we report several compounds that allosterically modulate hDAT binding and function, and we identify novel partial inhibitors of amphetamine-induced dopamine release.

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Discovery	US	RTI International Metals, Inc.	-
Nervous System Diseases	Discovery	US	Southern Research Institute	-

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