2-Amino-6-chloro-3,4-dihydroquinazoline (A6CDQ; 70) was developed as a novel 5-HT3 receptor antagonist. A6CDQ (70) produced antidepressant-like effects in the mouse tail suspension test (TST). 5-HT3 receptor was considered as one of potential mechanisms for the antidepressant-like effect. The goal of this work is to develop a model for the binding of A6CDQ (70) at 5-HT3 receptor, several structural features were examined which include: 1. Alkylation of the 2-amino with various alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and benzyl). 2. Bioisosteric substitution of quinazoline (70) with isoquinoline (226), quinoline (238), or tetraline (259). 3. An attempt to synthesize a quaternary structure of A6CDQ (70). 4. Synthesis of 2-methylthio analog of A6CDQ (70). 5. Examination of lipophilic/electronic effects (SAR) at 6-position of A6CDQ (70) (e.g. synthesis of iodo, t-butyl, cyclohexylmethyl and benzyl analogs). Moreover, molecular modeling study was conducted to determine the possible interactions of A6CDQ (70) and its analogs at molecular level, as well as radioligand binding assay was carried out at 5-HT3 receptor and x-ray crystal structural elucidation of A6CDQ (70) was performed to determine the position of the double bond (i.e. delocalized through three nitrogens or between N1, N3 or terminal N2 and C2).