5-HT3 receptor antagonism by anpirtoline, a mixed 5-HT1 receptor agonist/5-HT3 receptor antagonist.

Abstract

1. The aim of this study was to provide evidence that anpirtoline, which is an agonist at 5-HT1B and 5-HT1D receptors and also displays submicromolar affinity for 5-HT1A recognition sites, in addition, acts as an antagonist at 5-HT3 receptors. 2. In radioligand binding studies on rat brain cortical membranes, anpirtoline inhibited specific binding of [3H]-(S)-zacopride to 5-HT3 receptor recognition sites (pKi: 7.53). 3. In N1E-115 neuroblastoma cells in which [14C]-guanidinium was used as a tool to measure cation influx through the 5-HT3 receptor channel, the 5-HT-induced influx was concentration-dependently inhibited by anpirtoline. In this respect, anpirtoline mimicked other 5-HT3 receptor antagonists; the rank order of potency was ondansetron > anpirtoline > metoclopramide. 4. The concentration-response curve for 5-HT as a stimulator of [14C]-guanidinium influx was shifted to the right by anpirtoline (apparent pA2: 7.78). 5. In urethane-anaesthetized rats, anpirtoline inhibited (at lower potency than zacopride and tropisetron) the 5-HT- or phenylbiguanide-induced bradycardia (Bezold-Jarisch reflex), but did not induce this reflex by itself. 6. Intravenous infusion of cisplatin in the domestic pig caused a consistent emetic response which was antagonized by anpirtoline. 7. It is concluded that anpirtoline, which was previously characterized as a 5-HT1 receptor agonist also proved to be a 5-HT3 receptor antagonist in several experimental models and, hence, exhibits a unique pattern of properties at different 5-HT receptors.

• Authors: M Göthert, M Hamon, M Barann, H Bönisch, H Gozlan, R Laguzzi, P Metzenauer, B Nickel, I Szelenyi
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 114 Issue 2 Pg. 269-74 (Jan 1995) ISSN: 0007-1188 [Print] England
• PMID: 7881726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidepressive Agents
• Antiemetics
• Piperidines
• Pyridines
• Serotonin Antagonists
• Serotonin Receptor Agonists
• anpirtoline
• Serotonin
• Cisplatin

Topics

• Animals
• Antidepressive Agents (pharmacology)
• Antiemetics (pharmacology)
• Brain Neoplasms (metabolism)
• Cisplatin (pharmacology)
• Entorhinal Cortex (drug effects, metabolism)
• In Vitro Techniques
• Male
• Mice
• Neuroblastoma (metabolism)
• Piperidines (pharmacology)
• Pyridines (pharmacology)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Reflex (drug effects)
• Serotonin (metabolism)
• Serotonin Antagonists (metabolism, pharmacology)
• Serotonin Receptor Agonists (metabolism, pharmacology)
• Swine
• Tumor Cells, Cultured