Structural Modification From Agonists to Antagonists in the Synthesis of New 5-Hydroxytryptamine (5-HT3) Receptor Antagonists and Preliminary In-vitro Pharmacological Evaluation on Guinea-pig Ileum

Structural variations from agonists to their selective antagonists follow specific patterns. These patterns in reported molecules or drugs were analysed and common variation patterns, as possible principles to design new antagonistic drugs, were studied. The generalized structural modification patterns were successfully applied as guiding principles to synthesize two series of compounds with 5‐hydroxytryptamine (5‐HT3) receptor antagonistic activity. A series of new piperazinyl indolyl propanones bearing a methyl and an ethyl substituent, respectively, on the indolyl nitrogen was synthesized through a mannich reaction using 1‐substituted‐3‐acetyl indole 9 and 10 (1‐methyl‐3‐acetyl indole and 1‐ethyl‐3‐acetyl indole, respectively) as the substrate and various N‐4 unsubstituted arylpiperazines as the secondary amines. In‐vitro pharmacological evaluation of the synthesized compounds was performed on the guinea‐pig isolated longitudinal myenteric muscle plexus and antagonism at 10−5 M was compared with ondansetron. Compounds 9h‐j, arylpiperazinyl mannich bases of 9, showed moderate antagonism at the 5‐HT3 receptor.