Human Organic Cation Transporters (hOCTs) are an alternative/complementary clearance pathway for biogenic amines. Thus, OCTs could represent a new target for the development of mechanistically novel drugs to treat depression and related neuropsychiatric disorders. We have found that 2-amino-6-chloro-3,4-dihydroquinazoline (A6CDQ) possesses antidepressant-like activity in the mouse tail suspension test. A6CDQ lacks affinity for the serotonin transporter (SERT; Ki &gt;10,000 nM) but displayed inhibitory action (IC50 = 3.91 µM) at hOCT3s expressed in HEK293 cells. The des-Cl counterpart (ADQ) of A6CDQ showed significantly decreased inhibitory activity (IC50 = 12.16 µM) indicating a role for the Cl substituent. The 5-Cl (A5CDQ) and 7-Cl (A7CDQ) positional isomers of A6CDQ displayed comparable inhibitory action (IC50 = 0.88 and 5.93 μM, respectively) to A6CDQ implying that the position of the Cl-group might not be an important factor. To determine whether the 6-Cl group exerts its effect via its electronic or lipophilic character, we synthesized the 6-Me analog (A6MDQ) that bears an electron donating group as opposed to the electron withdrawing Cl-group. Methyl and chloro groups possess similar lipophilic (i.e., p = 0.56; 0.71, respectively), but opposite electronic, character. A6MDQ inhibited hOCT3 (IC50 = 2 μM) suggesting that the lipophilic character of the substituent plays an important role in the inhibitory actions of hOCT3. We generated the first 3-D graphics models of hOCT3 using the inorganic phosphate transporter (PDB:4J05) as a template and studied plausible binding modes for dihydroqinazolines. Hydropatic INTeraction (HINT) analysis for all the docked analogs revealed a positive relationship between hydrophobic interactions of the substituents and their potencies. Dihydroquinazolines represent a unique class of hOCT3 inhibitors lacking SERT affinity. [Supported in part by PeRQ Fund]

Dihydroquinazolines: A novel class of hOCT3 inhibitors

249th National Meeting (2015)

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