EXPLORING THE CONCEPT OF HUMAN OCT3 INHIBITORS AS A NOVEL CLASS OF ANTIDEPRESSANTS

• Main Author: Iyer, Kavita A
• Format: Others
• Published: VCU Scholars Compass 2016
• Subjects: OCT3; homology modeling; SAR; depression; quinazoline; tail suspension test; HINT; QSAR; hSERT; 5-HT3 receptors; Medicinal and Pharmaceutical Chemistry
• Online Access: http://scholarscompass.vcu.edu/etd/4607; http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=5674&context=etd

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.