Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test
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2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT3 serotonin receptor antagonist mechanism. Here, we investigated this further by examining a positional isomer of A6CDQ (i.e., A7CDQ).
Materials and methods
5-HT3 receptor and transporter activity (uptake-1 and uptake-2) were investigated using a variety of in vitro assays and the in vivo mouse tail suspension test (TST).
Although A7CDQ binds at 5-HT3 receptors with low affinity (Ki = 1975 nM) compared to A6CDQ (Ki = 80 nM), it retained 5-HT3 receptor antagonist action (IC50 = 5.77 and 0.26 μM, respectively). In the mouse TST A7CDQ produced antidepressant-like actions (ED50 = 0.09 mg/kg) comparable to that of A6CDQ. In addition, A6CDQ was found to be a 5-HT releasing agent (Km = 2.8 μM) at hSERT and a reuptake inhibitor (IC50 = 1.8 μM) at hNET, whereas A7CDQ was a weak reuptake inhibitor (Km = 43.6 μM) at SERT but a releasing agent (EC50 = 3.3 μM) at hNET. Moreover, A6CDQ and A7CDQ were potent inhibitors of uptake-2 (e.g.; OCT3 IC50 = 3.9 and 5.9 μM, respectively).
A simple shift of a substituent in a common quinazoline scaffold from one position to another (i.e., a chloro group from the 6- to the 7-position) resulted in a common action in the TST but via a somewhat different mechanism. A6CDQ and A7CDQ might represent the first members of a new class of potential antidepressants with a unique multi-modal mechanism of action.
Keywords5-HT3 receptors Uptake-1 Uptake-2 SERT NET OCT Electrophysiology TST Mice
Ki values were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. The authors thank the following: Prof. Richard A. Glennon for fruitful discussions and proof reading of the manuscript; Dr. Richard Young for his assistance with the TST and data analysis. Kavita Iyer was the recipient of a Lowenthal Award (2013-2015).
This study was supported in part by the A. D. Williams Trust funds (MD) and the VCU Presidential Research Quest Fund (MD and DHS) and National Institute of Health RO1 DA033930.
Compliance with ethical standards
Protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Virginia Commonwealth University.
Conflict of interest
The authors declare that they have no conflict of interest.
- Alix KE (2009) Novel analogs of m-chlorophenylguanidine as 5-HT3 receptor ligands. Virginia Commonwealth University, ThesisGoogle Scholar
- Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 27:699–711CrossRefGoogle Scholar
- Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen M-Y, Pieper U, Sali A (2007) Comparative protein structure modeling using modeler. Curr Protoc Bioinformatics 5(6):1–5.6.30Google Scholar
- Miyake A, Mochizuki S, Takemoto Y, Akuzawa S (1995) Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species. Mol Pharmacol 48:407–416Google Scholar
- Nash JF, Brodkin J (1991) Microdialysis studies on 3,4-methylmethamphetamine-induced dopamine release: effect of dopamine uptake inhibitors. J Pharmcol Exp Ther 259:820–825Google Scholar
- Solis E Jr, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH (2017) N-Alkylated analogs of 4-methylamphetamine (4-MA) differentially affect monoamine transporters and abuse liability. Neuropsychopharmacology 42:1950–1961CrossRefGoogle Scholar
- WHO (2018) Depression http://www.who.int/en/news-room/fact-sheets/detail/depression. Accessed 20 September 2018