Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors

doi:10.1016/0014-2999(95)00191-M

European Journal of Pharmacology

Volume 280, Issue 1, 23 June 1995, Pages 79-89

https://doi.org/10.1016/0014-2999(95)00191-M Get rights and content

Abstract

Erysodine, an erythrina alkaloid related to dihydro-β-erythroidine, was found to be a more potent inhibitor of [³H]cytisine binding at neuronal nicotinic acetylcholine receptors but a less potent inhibitor of [¹²⁵I]α-bungarotoxin binding at muscle-type nicotinic acetylcholine receptors than dihydro-β-erythroidine. Erysodine was a competitive, reversible antagonist of (−)-nicotine-induced dopamine release from striatal slices and inhibited (−)-nicotine-induced ⁸⁶Rb⁺ efflux from IMR-32 cells. Erysodine was equipotent with dihydro-β-erythroidine in the dopamine release assay but 10-fold more potent in the ⁸⁶Rb⁺ efflux assay, suggesting differential subtype selectivity for these two antagonists. Erysodine, systemically administered to mice, entered the brain and significantly attentuated nicotine's hypothermic effects and its anxiolytic-like effects in the elevated plus-maze test. There was greater separation between antagonist and toxic doses for erysodine than for dihydro-β-erythroidine, perhaps because of erysodine's greater selectivity for neuronal receptors. In rats, erysodine prevented both the early developing decrease and the late-developing increase in locomotor activity produced by (−)-nicotine. The potent and competitive nature of erysodine's antagonism together with its ability to enter the brain after systemic administration suggest that erysodine may be a useful tool in characterizing neuronal nicotinic acetylcholine receptors.

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Alkaloids of genus Erythrina: An updated review
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Genus Erythrina (Fabaceae) comprises several species, which are widely distributed in tropical and subtropical regions of the world. The plants of this genus exhibited significant role in traditional medicine targeting different diseases. Alkaloids and flavonoids were reported as the chief bioactive constituents of this genus with a wide range of biological activities. About 143 alkaloids were isolated from Erythrina sp. Anticonvulsant, anxiolytic, curare-like activity, insecticidal and cytotoxic activities were reported for Erythrina sp. alkaloids. The present work is an overview of the isolated alkaloids from Erythrina sp. with their reported biological activities.
Abbreviations: CHCl3: Chloroform; CNS: Central nervous system; DCM: Methylene chloride; DPPH: 2,2-Diphenyl-1-picrylhydrazyl; E.: Erythrina; ERα/β: Estrogen receptors α/β; EtOAc: Ethyl acetate; EtOH: Ethanol; Hep-G2: Human liver carcinoma cell lines; HIV: Human immunodeficiency virus; HL-60: Human promyelocytic leukemia cells; K-562: Human immortalized myelogenous leukemia cell line; LPS: Lipopolysaccharide; MeOH: Methanol; MOLT-4: Acute lymphoblastic leukemia cell line; nAChRs: nicotinic acetylcholine receptors; NO: Nitric oxide; NREM: non-rapid eye movement; Pet. ether: Petroleum ether; RBA: Receptor binder affinity; TRAIL: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand
Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors, decreases ethanol consumption in alcohol-preferring UChB rats
2018, Behavioural Brain Research
Citation Excerpt :
On the other hand, changes in NAc ACh levels have been suggested to be involved in modulating alcohol withdrawal [28]. Erysodine is a competitive antagonist of α4β2 nAChR and chemically it is an alkaloid obtained from Erythrina falcata related to dihydro-β-erythroidine (DHβE) [29]. Erysodine displaces [3H]-cytisine, a partial agonist with high affinity binding for α4β2 nAChR, in a concentration-dependent manner (Ki = 5 ± 1 nM) and inhibits ACh-stimulated current (IC50 = 20 nM) [30].
Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0 mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8 mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2 mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2 mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10 mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment.
Multiple binding sites in the nicotinic acetylcholine receptors: An opportunity for polypharmacolgy
2015, Pharmacological Research
For decades, the development of selective compounds has been the main goal for chemists and biologists involved in drug discovery. However, diverse lines of evidence indicate that polypharmacological agents, i.e. those that act simultaneously at various protein targets, might show better profiles than selective ligands, regarding both efficacy and side effects. On the other hand, the availability of the crystal structure of different receptors allows a detailed analysis of the main interactions between drugs and receptors in a specific binding site.
Neuronal nicotinic acetylcholine receptors (nAChRs) constitute a large and diverse family of ligand-gated ion channels (LGICs) that, as a product of its modulation, regulate neurotransmitter release, which in turns produce a global neuromodulation of the central nervous system. nAChRs are pentameric protein complexes in such a way that expression of compatible subunits can lead to various receptor assemblies or subtypes. The agonist binding site, located at the extracellular region, exhibits different properties depending on the subunits that conform the receptor. In the last years, it has been recognized that nAChRs could also contain one or more allosteric sites which could bind non-classical nicotinic ligands including several therapeutically useful drugs. The presence of multiple binding sites in nAChRs offers an interesting possibility for the development of novel polypharmacological agents with a wide spectrum of actions.
Functional expression of the α7 and α4-containing nicotinic acetylcholine receptors on the neonatal rat carotid body
2012, Neurochemistry International
The carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs.
Neonatal rat CBs were placed in a recording chamber for electrochemical recordings or disassociated for voltage-clamp studies on isolated cells. Fast nicotine superfusion increases catecholamine release from intact CBs. This response was diminished reversibly by the non-selective nAChR blocker hexamethonium, by the selective α7 blocker α-bungarotoxin and by the α4-containing nAChR blocker erysodine.
In isolated CB cells the nAChR agonists nicotine, acetylcholine and cytisine all evoke inward currents with similar potencies. The nicotine-evoked current was fully blocked by mecamylamine and partially inhibited by α-bungarotoxin or erysodine. However, the combination of both α-bungarotoxin an erysodine failed to suppress this response. Immunodetection studies confirm the presence of α7 and α4 subunits in isolated dopaminergic CB cells. Our results show that activation of α7 and/or α4-containing nAChR subtypes have the ability to regulate catecholamine release from intact CB due to activation of fast inward currents expressed in chemoreceptor cells. Therefore, our results suggest that both nAChR subtypes contribute to the cholinergic nicotinic regulation of catecholamine signaling in the carotid body system.
The alpha 9-nicotinic acetylcholine receptor serves as a molecular target for breast cancer therapy
2011, Journal of Experimental and Clinical Medicine
Citation Excerpt :
Other related functional drugs that target α4β2-nAChR also can be applied in smoking cessation,67–69 the treatment of attention-deficit hyperactivity disorder,70 cognitive dysfunction71 and depression.72 Neurotoxins are commonly used to distinguish between neuronal nAChR receptor subunit combinations.73,74 The neurotoxins lophotoxin, neosurugatoxin and α-bungarotoxin, and the alkaloids, dihydro-betaerythroidine (DHβE) and erysodine, are competitive nAChR antagonists that display selectivity for β2-containing nAChRs, particularly the α4β2 subtype.75
Tobacco is a substance that contains human carcinogens and may contribute to the risk of tumor formation in the lung and colon via nicotinic acetylcholine receptors (nAChRs). Cigarette smoke is a complex mixture of many compounds, including nicotine, which is the major active and addictive component of tobacco. Nicotine and its specific metabolized carcinogens directly bind to nAChRs on the cell membrane and trigger the nAChR signaling cascade. nAChRs, a family of ligand-gated ion channels that mediate the effects of the neurotransmitter acetylcholine, are among the best understood receptors. The α4β2-nAChR is known to exist in the central nervous system and functions as a transmitter, whereas the α7-nAChR is a well-established molecule that is involved in lung cancer tumorigenesis. Previously, however, there had been no direct evidence to provide a link between tobacco carcinogens and cellular molecules involved in breast tumorigenesis. Recently, two large cohort epidemiological studies undertaken in the United States and Japan have indicated that breast cancer risk is associated with both active and passive smoking. Analysis of α9-nAChR expression in clinical tumor tissues has indicated that the α9-nAChR is important for tumor carcinogenesis in vivo and nicotine-induced transformation of normal human breast epithelial cells in vitro. Long-term exposure to estrogen and nicotine significantly increases α9-nAChR expression and forms a positively regulated loop and that can be blocked by several chemicals and natural compounds. In this review, we describe recent advances in the understanding of the assembly, activity and biological functions of nicotinic receptors, as well as developments in the therapeutic application of nicotinic receptor ligands.

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European Journal of Pharmacology

Abstract

References (28)

Some quantitative uses of drug antagonists

Br. J. Pharmacol.

The binding of agonists to brain muscarinic receptors

Mol. Pharmacol.

Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze

Eur. J. Pharmacol.

Effects of mutations of Torpedo acetylcholine receptor α₁ subunit residues 184–200 on α-bungarotoxin binding in a recombinant fusion protein

Biochemistry

Chronic central nicotinic blockade after a single administration of the bisquaternary ganglion-blocking drug chlorisondamine

Br. J. Pharmacol.

Mecamylamine blockade of nicotinic responses: evidence for two brain nicotinic receptors

Pharmacol. Biochem. Behav.

Effects of central nicotinic cholinergic receptor blockade produced by chlorisondamine on learning and memory performance in rats

Behav. Neural Biol.

Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors

Trends Pharmacol. Sci.

Cloning and functional expression of alpha 9: a novel acetylcholine-gated ion channel

Properties of γ-aminobutyric acid receptor binding in rat brain synaptic membrane fractions

Brain Res.

A subtype of nicotinic cholinergic receptor is composed of α₄ and β₂ subunits and is upregulated by chronic nicotine treatment

Mol. Pharmacol.

Identification of the alpha-subunit half-cystine specifically labeled by an affinity reagent for the acetylcholine receptor binding site

J. Biol. Chem.

Actions of Erythrina americana, a possible curare substitute

J. Pharmacol. Exp. Ther.

Both α- and β-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors

J. Neurosci.

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Role of the glycoprotein thorns in anxious effects of rabies virus: Evidence from an animal study

Alkaloids of genus Erythrina: An updated review