X-Ray Crystal Structure of a 2-Amino-3,4-dihydroquinazoline 5-HT3 Serotonin Receptor Antagonist and Related Analogs.

Certain 2-amino-3,4-dihydroquinazolines bind at 5-HT3 serotonin receptors and act as antagonists (e.g. 6-chloro) whereas others bind with little to no affinity and lack functional activity (e.g. 8-chloro). The purpose of this investigation was to gain insight as to why this might be the case. X-Ray crystallographic studies revealed that the N-C-N distances in the examined analogs are nearly identical (1.31 - 1.34 Å), suggesting that differences in N-C-N delocalization does not account for differences in affinity/action. Homology modeling hydrophatic interactions (HINT) analysis revealed that the 6-chloro analog formed a greater number, and more favorable, interactions with the receptor, whereas the 8-chloro analog formed fewer, and unfavorable, interactions. The affinity and activity of the 6-chloro quinazoline relative to its 8-chloro counterpart are unrelated to the N-C-N delocalization pattern but might be related to specific (favorable and unfavorable) interactions of quinazoline substituents with certain receptor features as determined by HINT analysis.