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-HTIB and 5-HT,D receptors and also displays submicromolar affinity for 5-HTlA 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 NIE-115 neuroblastoma cells in which ['4C]-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 ['4C]-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-HT, 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.

Analysis of the Role of the 5-HT1B Receptor in Spatial and Aversive Learning in the Rat

“…In comparison, anpirtoline only shows a five-fold preference for the rat 5-HT 1B receptor (K i ¼ 28 nM) vs the rat 5-HT 1A (K i ¼ 150 nM) and a 50-fold preference vs the 5-HT 2 (K i ¼ 1.49 mM) receptor (Schlicker et al, 1992). Furthermore, anpirtoline has been shown to act as a 5-HT 3 antagonist in both binding assays (pK i ¼ 7.53) and 5-HT IB receptors and learning M Å hlander-Lüttgen et al behavioral studies (Gothert et al, 1995). This implies that anpirtoline, at least at high doses, could stimulate the 5-HT 1A receptor, evidenced by the observation that animals treated with anpirtoline displayed parts of the serotonin syndrome (flat body posture) during the WM task (see Results section).…”

“…NAS-181 has been demonstrated to enhance 5-HT metabolism in the rat brain in a dose-dependent manner (0.1-20 mg/kg, s.c.), with maximal effects 60 min after the injection (Stenfors et al, 2000). The effects of NAS-181 on performance in the WM and PA tasks as well as the ability of the compound to block or attenuate the effects of a nonselective 5-HT 1B agonist, anpirtoline were investigated (Gothert et al, 1995;Schlicker et al, 1992;Swedberg et al, 1992). The serotonergic and cholinergic systems appear to interact in various aspects of learning and memory (Steckler and Sahgal, 1995).…”

Synthesis, Analgesic Activity, and Binding Properties of Some Epibatidine Analogs with a Tropine Skeleton

“…Polymeropoulos and Kutscher [19] found that some centrally acting analgesics with different mode of activity, including epibatidine and anpirtoline [20][21][22][23] , have similar energetically low-lying conformations. Antinociceptive activity of epibatidine is caused by its strong agonistic activity on neuronal nicotinic receptors [24] while it has no effect on both serotonin type l and muscarinic receptors.…”

Synthesis and Analgesic Activity of Some Deaza Derivatives of Anpirtoline

“…It was found to be a mixed 5-HT1 receptor agonist/5-HT3 receptor antagonist. The 5-HT1B agonistic activity is expected to be its principal mode of action [4,5] . In spite of its pronounced analgesic activity, the drug has not been introduced into the market, probably due to unspecified side effects.…”