VA21B7 (3-[2-(4'-piperonylpiperazinyl) indolyl] carboxaldehyde) was synthesized as a potential
5-HT3 receptor antagonist. Even though
VA21B7 showed a higher affinity towards 5-HT3 receptors as compared to other receptors studied, it was not a potent
5-HT3 receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remarkable
anxiolytic-like effect was found at doses of 2-500 micrograms/kg IP and also at low oral doses, in the microgram range. These
drug doses did not produce any significant effect on spontaneous motor activity of mice. The
anxiolytic profile of
VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished-drinking.
VA21B7 was compared with standard
5-HT3 receptor antagonists such as
ondansetron,
tropisetron and
granisetron, with the 5-HT1A agent
buspirone and with
diazepam. In the plus-maze,
VA21B7 showed an
anxiolytic-like profile after doses of 0.25-0.5 mg/kg IP or 2-4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze.
Diazepam,
granisetron and
tropisetron were also effective in this test but not
ondansetron and
buspirone.
VA21B7 was also able to release suppressed behaviour in the punished-drinking test. The dose-response curve was bell-shaped with a peak at 2-4 mg/kg. At variance with other studies,
5-HT3 receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped.
VA21B7 was not
anticonvulsant like
diazepam, its
anxiolytic action in the light/dark test was not
flumazenil-sensitive and there was no rebound anxiogenic effect on withdrawal from chronic
VA21B7 treatment for 15 consecutive days. Moreover,
VA21B7 was not amnesic like the
benzodiazepines but low doses of 2-4 mg/kg reduced the
memory deficits induced in rats by
scopolamine. Much higher doses were necessary to decrease spontaneous motor activity in rats. Since
VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential interest as an
anxiolytic in humans.