Differential activity of decynium-22 analogs: novel targets for probing low-affinity/high-capacity biogenic amine transporters

Abstract

We study neurotransmitter clearance by low-affinity, high-capacity uptake-2 transporters. This family includes plasma membrane monoamine transporter (PMAT) and three organic cation transporter isoforms (OCT1-3). We have shown uptake-2 transporters limit the effectiveness of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine. Discerning the transporter type(s) involved is restricted by the lack of highly selective ligands. This project examines the pharmacological characteristics of novel uptake-2 compounds. Activity of ANSTO analogs, structurally based on the non-selective inhibitor decynium 22 (D22), was tested in human OCT3-HEK cells. Ligand competitions of [3H]MPP+ uptake were measured in whole, attached cells. Compared to D22, dose-responses of ANSTO compounds shifted 1- or 2 log-rightward, indicating reduced potency to inhibit OCT3 mediated [3H]MPP+ uptake. ANSTO analogs displayed similar potencies to corticosterone and may have higher selectivity at alternate uptake 2 subtypes. © 2015 Federation of American Societies for Experimental Biology (FASEB)