Abstract: According to the principle of bioisosterism and the Evans'pharmacophore model of 5-HT₃ receptor antagonists, twelve derivatives of tetramethylpyrazine were synthesized. The structures of the compounds were confirmed by MS, ¹H NMR and HRMS. All the target compounds are unreported. The preliminary activity test showed that most of the compounds had fairly potent 5-HT₃ receptor antagonistic activities, especially compound 3c. And the conformational analysis showed that the active conformation of the compounds was quite fitted to the Evans'pharmacophore model. This indicates that besides the three pharmacophoric elements, the aromatic ring and the substituents attached may affect the bioactivities of the compounds.

Key words: Derivatives of tetramethylpyrazine, 5-HT₃ Receptor antagonistic inhibitor, Structure-activity relationship(SAR)