The 2-Amino-3,4-dihydroquinazoline Molecular Scaffold as Novel OCT3 Inhibitor

Organic cation transporters 1-3 (OCTs 1-3), especially OCT3, have emerged as "high-capacity" uptake transporters for the aminergic neurotransmitters serotonin, norepinephrine, and dopamine from the synapse. We previously reported the 6- and 7-chloro analogs of 2-aminodihydroquinazoline (i.e., A6CDQ and A7CDQ, respectively) as novel inhibitors of OCTs. Here, we synthesized and evaluated a focused series of analogs bearing substituents at the aryl 5-, 6-, 7-, or 8-position. All compounds inhibited action at OCT1, OCT2, and especially OCT3. The present study centered primarily on OCT3 because it has been implicated in the action of antidepressants. Through this work, seven analogs were found to be more potent, or at least equipotent, at OCT3 than A6CDQ or A7CDQ. Additionally, three analogs were found, as with A6CDQ and A7CDQ, to be active in the mouse tail suspension test - a well-established proxy for evaluating potential antidepressant-like action. Our 3D molecular modeling studies identified SER474, ASP478, and CYS477 as key residues in the binding interactions of the 2-aminodihydroquinazoline (ADQ) chemotype at OCT3. Furthermore, the binding mode of ADQ analogs and the extensive size of the binding pocket warrant further examination of the scaffold, and particularly of additional aryl substituents to exploit this region of bulk tolerance.