5-HT_3 receptor antagonism by anpirtoline, a mixed 5-HT_1 receptor agonist/5-HT_3 receptor antagonist

摘要

1. The aim of this study was to provide evidence that anpirtoline, which is an agonist at 5-HT_(1B) and 5-HT_(1D) receptors and also displays submicromolar affinity for 5-HT_(1A) recognition sites, in addition, acts as an antagonist at 5-HT_3 receptors. 2. In radioligand binding studies on rat brain cortical membranes, anpirtoline inhibited specific binding of [~3H]-(S)-zacopride to 5-HT_3 receptor recognition sites (pK_i: 7.53). 3. In NlE-115 neuroblastoma cells in which [~(14)C]-guanidinium was used as a tool to measure cation influx through the 5-HT_3 receptor channel, the 5-HT-induced influx was concentration-dependently inhibited by anpirtoline. In this respect, anpirtoline mimicked other 5-HT_3 receptor antagonists; the rank order of potency was ondansetron> anpirtoline> metoclopramide. 4. The concentration-response curve for 5-HT as a stimulator of [~(14)C]-guanidinium influx was shifted to the right by anpirtoline (apparent pA_2: 7.78). 5. In urethane-anaesthetized rats, anpirtoline inhibited (at lower potency than zacopride and tropiset-ron) 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-HT_1 receptor agonist also proved to be a 5-HT_3 receptor antagonist in several experimental models and, hence, exhibits a unique pattern of properties at different 5-HT receptors.