Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency

The Journal of Pharmacology and Experimental Therapeutics
R B RothmanM H Baumann

Abstract

Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that SRI-9804 [N-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [(125)I]RTI-55 ([(125)I]3β-(4'-iodophenyl)tropan-2β-carboxylic acid methyl ester) binding and [(3)H]dopamine ([(3)H]DA) uptake, slow the dissociation rate of [(125)I]RTI-55 from the DAT, and allosterically modulate d-amphetamine-induced, DAT-mediated DA release. We synthesized and evaluated the activity of >500 analogs of these ligands and report here on 36 selected compounds. Using synaptosomes prepared from rat caudate, we conducted [(3)H]DA uptake inhibition assays, DAT binding assays with [(3)H]WIN35428 ([(3)H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane), and DAT-mediated release assays with either [(3)H]MPP(+) ([(3)H]1-methyl-4-phenylpyridinium) or [(3)H]DA. We observed three groups of [(3)H]DA uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) full-efficacy agents with a two-site fit, and 3) partial-efficacy agents with a one-site fit-the focus of further studies. These agents partially inhibite...Continue Reading

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Citations

Aug 29, 2018·The Journal of Pharmacology and Experimental Therapeutics·Megan J MoerkeS Stevens Negus
Dec 21, 2017·Current Protocols in Pharmacology·Shaili Aggarwal, Ole V Mortensen
Dec 21, 2017·Current Protocols in Pharmacology·Shaili Aggarwal, Ole V Mortensen
Mar 29, 2019·Current Opinion in Structural Biology·Vikas Navratna, Eric Gouaux
May 31, 2020·Trends in Pharmacological Sciences·Marco NielloHarald H Sitte
Aug 21, 2018·Neurochemistry International·Michael J TomlinsonRoxanne A Vaughan
Apr 23, 2021·ACS Chemical Neuroscience·Charles AdeniranChang-Guo Zhan

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