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Psychopharmacology

, Volume 236, Issue 7, pp 2093–2104 | Cite as

Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test

  • Kavita A. Iyer
  • Katie Alix
  • Jose M. Eltit
  • Ernesto SolisJr.
  • Xiaolei Pan
  • Malaika D. Argade
  • Shailesh Khatri
  • Louis J. De Felice
  • Douglas H. Sweet
  • Marvin K. Schulte
  • Małgorzata DukatEmail author
Original Investigation
  • 197 Downloads

Abstract

Rationale

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).

Results

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).

Conclusions

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.

Keywords

5-HT3 receptors Uptake-1 Uptake-2 SERT NET OCT Electrophysiology TST Mice 

Notes

Acknowledgments

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).

Funding information

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.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kavita A. Iyer
    • 1
  • Katie Alix
    • 1
  • Jose M. Eltit
    • 2
  • Ernesto SolisJr.
    • 2
  • Xiaolei Pan
    • 3
  • Malaika D. Argade
    • 1
  • Shailesh Khatri
    • 4
  • Louis J. De Felice
    • 2
  • Douglas H. Sweet
    • 3
  • Marvin K. Schulte
    • 5
  • Małgorzata Dukat
    • 1
    Email author
  1. 1.Department of Medicinal Chemistry, School of PharmacyVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of Physiology and Biophysics, School of MedicineVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Pharmaceutics, School of PharmacyVirginia Commonwealth UniversityRichmondUSA
  4. 4.Department of Pharmaceutical Sciences, Philadelphia College of PharmacyUniversity of SciencesPhiladelphiaUSA
  5. 5.Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Kasiska Division of Health SciencesIdaho State UniversityPocatelloUSA

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