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-HT 3 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. Image 1 • Certain quinazoline analogs bind at 5-HT 3 serotonin receptors; certain other do not. • X-Ray structures were solved to determine if delocalization was involved in their binding. • Modeling suggests that 6-Cl-2-amino-3,4-dihydroquinazoline binds in a positive fashion vs its 8-Cl positional isomer. [ABSTRACT FROM AUTHOR]