213 117 117 2 2 I. Artaiz G. Romero A. Zazpe B. Lasheras J. Del Río A. Monge J. M. Calderó J. Roca Department of Pharmacology, Schools of Medicine and Pharmacy University of Navarra Apdo. 273 E-31080 Pamplona Spain Department of Organic Chemistry, CIFA University of Navarra E-31080 Pamplona Spain Vita Research Department Barcelona Spain Abstract VA21B7 (3-(2-(4′-piperonylpiperazinyl) indolyl) carboxaldehyde) was synthesized as a potential 5-HT 3 receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT 3 receptors as compared to other receptors studied, it was not a potent 5-HT 3 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 µg/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-HT 3 receptor antagonists such as ondansetron, tropisetron and granisetron, with the 5-HT 1A 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-HT 3 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.
Psychopharmacology – Springer Journals
Published: Jan 1, 1995
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