Ciproxifan

Ciproxifan is a novel and potent antagonist of histamine H3-receptor with a IC50 value of 9.2±1.8nM [1].

Ciproxifan has shown the in-vitro antagonistic action to H3-receptor with a IC50 value of 9.2±1.8nM. In addition, Ciproxifan has been reported to competitively antagonize the (R) α-MeHA induced relaxation of electrically stimulated guinea pig ileum longitudinal muscle. Besides, Ciproxifan has been revealed to have the effect on [125I]iodoproxyfan binding with a Ki value of 0.7±0.2 nM. Apart from these, Ciproxifan has been found to be a selective antagonist with pKi values of 9.3, 4.9, 4.6, 5.5, 5.4, 4.9, <5.0, 4.8, <5.5 and <5.7 for H3, H2, H1, muscarinic M3, adrenergic α1D, β1, serotonin 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4, respectively [1].

References:
[1] Ligneau X1, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, Schunack W, Schwartz J. Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist. J Pharmacol Exp Ther. 1998 Nov; 287(2):658-66.

Ciproxifan, an H3 receptor antagonist, improves short-term recognition memory impaired by isoflurane anesthesia.[Pubmed:27193325]

J Anesth. 2016 Aug;30(4):684-90.

BACKGROUND: Exposure to volatile anesthetics has been reported to cause temporary or sustained impairments in learning and memory in pre-clinical studies. The selective antagonists of the histamine H3 receptors (H3R) are considered to be a promising group of novel therapeutic agents for the treatment of cognitive disorders. The aim of this study was to evaluate the effect of H3R antagonist Ciproxifan on isoflurane-induced deficits in an object recognition task. METHODS: Adult C57BL/6 J mice were exposed to isoflurane (1.3 %) or vehicle gas for 2 h. The object recognition tests were carried at 24 h or 7 days after exposure to anesthesia to exploit the tendency of mice to prefer exploring novel objects in an environment when a familiar object is also present. During the training phase, two identical objects were placed in two defined sites of the chamber. During the test phase, performed 1 or 24 h after the training phase, one of the objects was replaced by a new object with a different shape. The time spent exploring each object was recorded. RESULTS: A robust deficit in object recognition memory occurred 1 day after exposure to isoflurane anesthesia. Isoflurane-treated mice spent significantly less time exploring a novel object at 1 h but not at 24 h after the training phase. The deficit in short-term memory was reversed by the administration of Ciproxifan 30 min before behavioral training. CONCLUSION: Isoflurane exposure induces reversible deficits in object recognition memory. Ciproxifan appears to be a potential therapeutic agent for improving post-anesthesia cognitive memory performance.

The Effect of Subchronic Dosing of Ciproxifan and Clobenpropit on Dopamine and Histamine Levels in Rats.[Pubmed:26379444]

J Exp Neurosci. 2015 Aug 31;9:73-80.

The present study was designed to investigate the effect of once daily for 7-day (subchronic treatment) dosing of histamine H3 receptor antagonists, Ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p), including clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively, on MK-801(0.2 mg/kg, i.p.)-induced locomotor activity, and dopamine and histamine levels in rats. Dopamine and histamine levels were measured in striatum and hypothalamus, respectively, of rat brain. Atypical and typical antipsychotics were used to serve as clinically relevant reference agents to compare the effects of the H3 receptor antagonists. MK-801-induced increase of horizontal activity was reduced with CPX and CBP. The attenuation of MK-801-induced locomotor hyperactivity produced by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised dopamine levels in the striatum, which was reduced in rats pretreated with CPX and CBP. CPZ also lowered striatal dopamine levels, though the decrease was less robust compared to CLZ, CPX and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increase in histamine levels in the hypothalamus compared to the MK-801 treatment alone. Histamine H3 receptor agonist, R-alpha methylhistamine (10 mg/kg, i.p.) counteracted the effects of CPX and CBP. In conclusion, the subchronic dosing of CPX/CBP suggests some antipsychotic-like activities as CPX/CBP counteracts the modulatory effects of MK-801 on dopamine and histamine levels and prevents MK-801-induced hyperlocomotor behaviors.

Ciproxifan, a histamine H3 receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus.[Pubmed:28132918]

Toxicol Appl Pharmacol. 2017 Mar 15;319:12-21.

Ciproxifan is an H3 receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, Ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca(2+)-dependent glutamate release and cytosolic Ca(2+) concentration elevation but did not affect the membrane potential. The inhibitory effect of Ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker omega-conotoxin MVIIC, but was not affected by the intracellular Ca(2+)-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A2 (PLA2) inhibitor OBAA, prostaglandin E2 (PGE2), PGE2 subtype 2 (EP2) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of Ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The Ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, Ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that Ciproxifan, acting through the blockade of Gi/Go protein-coupled H3 receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca(2+) entry by diminishing PLA2/PGE2/EP2 receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B.[Pubmed:28084411]

Sci Rep. 2017 Jan 13;7:40541.

Ciproxifan is a well-investigated histamine H3 receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer's disease. In a screening for potential monoamine oxidase A and B inhibition Ciproxifan showed efficacy on both enzyme isoforms. Further characterization of Ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by Ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of Ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since Ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands.

Ciproxifan(FUB-359) is a highly potent and selective histamin H3-receptor antagonist with IC50 of 9.2 nM, with low apparent affinity at other receptor subtypes.

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