Doctor of Philosophy
Dr. Małgorzata Dukat
The Dukat laboratory developed 2-amino-6-chloro-3,4-dihydroquinazoline (A6CDQ) as a 5-HT3 receptor ligand. A6CDQ and one of its positional isomers, the 7-chloro analog A7CDQ, produced antidepressant-like effects in the mouse tail suspension test (TST). We investigated and systematically ruled out a solely 5-HT3 receptor or hSERT mediated mechanism of antidepressant-like effect for both A6CDQ and A7CDQ.
The role of organic cation transporter 3 (OCT3) as an alternative mechanism in the regulation of neurotransmitters including serotonin (5-HT) and the therapeutic potential of targeting hOCT3 to achieve antidepressant effects has been established. By virtue of possessing protonatable nitrogen atoms, 2-aminodihyroquinazolines could potentially exhibit activity at OCT3. A major goal of our present study was to explore the non-serotonergic mechanism of antidepressant-like effects and to study the as yet unexplored structure-activity-relationships (SARs) at OCT3. We examined the role of i) the chloro group, ii) the methylene bridge and iii) electronic/lipophilic effects at the 6-position.
We developed the first 3-D homology models of both the human and mouse orthologs of OCT3, conducted docking studies and HINT analysis, and identified critical amino acid residues interacting with 2-aminodihydroquinazoline analogs at hOCT3 and mOCT3. Retention of antidepressant-like activity in the mouse and potential locomotor stimulant effects for TST-active doses were thoroughly investigated.
We have successfully investigated initial SAR of 2-aminodihydroquinazolines at hOCT3 and generated the first 3-D homology models of hOCT3 and mOCT3. Highly potent and selective compounds could potentially be developed as radioligands to probe the binding site of OCT3 and as a mechanistically novel class of antidepressants.
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