5-HT3 receptor antagonism by anpirtoline, a mixed 5-HT1 receptor agonist/5-HT3 receptor antagonist.
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.
Göthert
M
M
Inst. Pharmacol. Toxicol., Univ. Bonn, Germany.
Hamon
M
M
Barann
M
M
Bönisch
H
H
Gozlan
H
H
Laguzzi
R
R
Metzenauer
P
P
Nickel
B
B
Szelenyi
I
I
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000932:Antiemetics / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine; D014407:Tumor Cells, Cultured
D000928:Antidepressive Agents; D000932:Antiemetics; D010880:Piperidines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C075631:anpirtoline; D012701:Serotonin; D002945:Cisplatin