Novel decynium 22 analogs are potent and selective inhibitors of organic cation transporter-3

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dc.contributor.authorFraser-Spears, Ren_AU
dc.contributor.authorOwens, WAen_AU
dc.contributor.authorWyatt, NAen_AU
dc.contributor.authorKrause-Heuer, AMen_AU
dc.contributor.authorGreguric, Ien_AU
dc.contributor.authorCallaghan, PDen_AU
dc.contributor.authorFraser, BHen_AU
dc.contributor.authorKoek, Wen_AU
dc.contributor.authorDaws, LCen_AU
dc.date.accessioned2023-01-27T00:52:10Zen_AU
dc.date.available2023-01-27T00:52:10Zen_AU
dc.date.issued2015-12-03en_AU
dc.date.statistics2022-09-27en_AU
dc.description.abstractBackground: Low-affinity, high-capacity transporters for biogenic amines help regulate neurotransmitter homeostasis. They include the plasma membrane monoamine transporter (PMAT) and three organic cation transporter isoforms (OCT1-3). Our published data, using decynium-22 (D22), a non-selective blocker of PMAT and OCTs, suggests OCT3 and/or PMAT limit the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRI). To aid in discerning the precise transporter(s) involved, we have characterized newly synthesized D22 analogs to identify PMAT and OCT isoform selective compounds. Methods: Effects of ANSTO analogs on locomotor activity and antidepressant-like behaviors were assessed in adult male, wild type (WT) mice using beam break measurements and the tail suspension test (TST). The activity of 7 analogs (ANSTO 301-307) to inhibit [3H]MPP+ uptake were measured in synaptosomes and HEK cells stably expressing human PMAT, OCT2 or OCT3. Results: Unlike D22, locomotor activity was not fully suppressed at higher doses up to 1.0 mg/kg, of ANSTO analogs 301, 303-306, and up to 10 mg/kg for ANSTO 307. Similarly to D22, ANSTO compounds (up to 1.0 mg/kg) did not show an antidepressant-like effect in the TST when given alone, however at 3.2 mg/kg, ANSTO 305 and 306 produced antidepressant-like effects. In synaptosomes, all ANSTO compounds, with the exception of analogs 303 and 306, inhibited [3H]MPP+ uptake more potently than D22. In contrast, ANSTO compounds were less potent than D22 and shifted [3H]MPP+ uptake 1- or 2 log-rightward in OCT3-HEK cells. ANSTO analogs displayed similar potencies to corticosterone, which is a blocker of OCT3. ANSTO analogs inhibited [3H]MPP+ uptake through OCT3 more favorably than PMAT (except analog 302) and OCT2 (except analogs 301 & 302). Conclusions: The significantly enhanced potency for several ANSTO compounds to inhibit [3H]MPP+ uptake in OCT3-HEK cells suggests these compounds may have higher affinity for OCT3 than PMAT or OCT2. Studies measuring behavioral outcomes and competition assays with an SSRI in WT, OCT3 knockout & PMAT knockout mice for physiological comparisons to cell overexpression systems are underway. These studies will reveal more about the pharmacological profile of these novel compounds and their potential therapeutic application to treat disorders, such as depression and drug abuse. © 2022 Springer Nature Limiteden_AU
dc.identifier.citationFraser-Spears, R., Owens, W. A., Wyatt, N., Krause-Heuer, A. M., Greguric. I., Callaghan, P. D.., Fraser, B. H., Koek, W., & Daws, L. (2015). Novel decynium 22 analogs are potent and selective inhibitors of organic cation transporter-3. Poaster presented to the 54th Annual Meeting the American College of Neuropsychnpharmacology, December 6-10, 2015, Diplomat Resort and Spa Hollywood, Florida. In Poster Session II. Neuropsychopharmacol 40(1), S272–S442 (2015). doi:10.1038/npp.2015.326en_AU
dc.identifier.conferenceenddate10 December 2015en_AU
dc.identifier.conferencename54th Annual Meeting the American College of Neuropsychnpharmacologyen_AU
dc.identifier.conferenceplaceFlorida, USAen_AU
dc.identifier.conferencestartdate6 December 2015en_AU
dc.identifier.issn1740-634Xen_AU
dc.identifier.issue1en_AU
dc.identifier.journaltitleNeuropsychopharmacologyen_AU
dc.identifier.otherT61en_AU
dc.identifier.paginationS272-S442en_AU
dc.identifier.urihttps://doi.org/10.1038/npp.2015.326en_AU
dc.identifier.urihttps://apo.ansto.gov.au/dspace/handle/10238/14528en_AU
dc.identifier.volume40en_AU
dc.language.isoenen_AU
dc.publisherSpringeren_AU
dc.subjectEnzyme inhibitorsen_AU
dc.subjectCationsen_AU
dc.subjectUptakeen_AU
dc.subjectAntidepressantsen_AU
dc.subjectPsychotropic drugsen_AU
dc.subjectSerotoninen_AU
dc.subjectOrganic compoundsen_AU
dc.subjectANSTOen_AU
dc.titleNovel decynium 22 analogs are potent and selective inhibitors of organic cation transporter-3en_AU
dc.typeConference Posteren_AU
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