scholarly journals Minimal Structural Changes Determine Full and Partial Nicotinic Receptor Agonist Activity for Nicotine Analogues

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2684 ◽  
Author(s):  
Juan Pablo Gonzalez-Gutierrez ◽  
Martin Hodar ◽  
Franco Viscarra ◽  
Pablo Paillali ◽  
Nicolás Guerra-Díaz ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Changes ◽  
Radioligand Binding ◽  
Anxiety And Depression ◽  
Agonist Activity ◽  
Binding Assays ◽  
Partial Agonists ◽  
Electrode Voltage ◽  
Clonal Cell Lines

Neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4β2 nAChRs subtypes. The most important therapeutic use for α4β2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4β2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4β2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.

scholarly journals Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3808
Author(s):  
Juan Pablo González-Gutiérrez ◽  
Hernán Armando Pessoa-Mahana ◽  
Patricio Ernesto Iturriaga-Vásquez ◽  
Miguel Iván Reyes-Parada ◽  
Nicolas Esteban Guerra-Díaz ◽  
...  
Keyword(s):  
Binding Site ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Docking Studies ◽  
Binding Assays ◽  
Serotonin Transporters ◽  
Paroxetine Binding ◽  
Compound 21 ◽  
Binding Percentage

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 μM for α4β2 nAChR and 0.075 ± 0.009 μM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

scholarly journals The Caenorhabditis elegans DEG-3/DES-2 Channel Is a Betaine-Gated Receptor Insensitive to Monepantel

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 312
Author(s):  
Tina V. A. Hansen ◽  
Heinz Sager ◽  
Céline E. Toutain ◽  
Elise Courtot ◽  
Cédric Neveu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Parasitic Nematode ◽  
Nematode Species ◽  
Xenopus Laevis Oocytes ◽  
Allosteric Modulators ◽  
C Elegans ◽  
Electrode Voltage ◽  
Insight Into

Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode Caenorhabditis elegans, where it is required for normal motility. Worm motility is mediated by nicotinic acetylcholine receptors (nAChRs), including subunits from the nematode-specific DEG-3 group. Not all types of nAChRs in this group are associated with motility, and one of these is the DEG-3/DES-2 channel from C. elegans, which is involved in nociception and possibly chemotaxis. Interestingly, the activity of DEG-3/DES-2 channel from the parasitic nematode of ruminants, Haemonchus contortus, is modulated by monepantel and its sulfone metabolite, which belong to the amino-acetonitrile derivative anthelmintic drug class. Here, our aim was to advance the pharmacological knowledge of the DEG-3/DES-2 channel from C. elegans by functionally expressing the DEG-3/DES-2 channel in Xenopus laevis oocytes and using two-electrode voltage-clamp electrophysiology. We found that the DEG-3/DES-2 channel was more sensitive to betaine than ACh and choline, but insensitive to monepantel and monepantel sulfone when used as direct agonists and as allosteric modulators in co-application with betaine. These findings provide important insight into the pharmacology of DEG-3/DES-2 from C. elegans and highlight the pharmacological differences between non-parasitic and parasitic nematode species.

scholarly journals Activation of Alpha7 Nicotinic Acetylcholine Receptors Reduce Chronic Pain-induced Anxiety and Depression-Like Behaviors via WNT/β-Catenin Pathway

2021 ◽  
Author(s):  
Xingrui Gong ◽  
Yongmei Chen ◽  
Rongmei Fan ◽  
Meihua Cai ◽  
Mazhong Zhang
Keyword(s):  
Chronic Pain ◽  
Inflammatory Response ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Brain Inflammation ◽  
Anxiety And Depression ◽  
Common Mechanism ◽  
Cold Response ◽  
Nicotinic Acetylcholine ◽  
Anti Inflammatory

Abstract Chronic pain frequently leads to anxiety, depression and microglia-related inflammation is the common mechanism for chronic pain and psychiatric disorders. Activation of alpha 7 nicotinic acetylcholine (α7 nAch) receptor suppresses microglia-related inflammation. Thus, we evaluated the activation of α7 nAch receptors on chronic pain-induced anxiety- and depression-like behaviors and explored the potential mechanisms. Open field, sucrose preference, and pain behavior tests (paw withdrawal threshold, and cold response to acetone) were evaluated in male Wistar rats that received spared nerve injury (SNI) and complete Freund’s adjuvant (CFA) into the unilateral ankle articular cavity. The effect of intracerebroventricular (ICV) injection of α7 nAch receptor agonist PHA and α7 nAch receptor antagonist on anxiety and depression-like behaviors and cytokines expression were examined. Cytokines in medial prefrontal cortex (mPFC), basolateral amygdala (BA), and ventral hippocampus (VH) were measured using enzyme-linked immune absorbent assay. SNI surgery and CFA injection induced anxiety- and depression-like behaviors, and ICV injection of PHA reduced that anxiety- and depression-like behaviors. SNI surgery and CFA injection skewed the mPFC, BA, and VH to a pro-inflammatory response and ICV injection of PHA shift brain to an anti-inflammatory response in those sites. The anti-depressive effect and anti-inflammatory effect of PHA were reversed by WNT/β-catenin inhibitor. Activation of alpha7 nicotinic acetylcholine receptors reduces chronic pain-induced anxiety- and depression-like behaviors, the mechanisms may be attributed to the activation of WNT/β-catenin pathway and suppression of brain inflammation.

scholarly journals Tetrapeptide Ac-HAEE-NH2 Protects α4β2 nAChR from Inhibition by Aβ

2020 ◽  
Vol 21 (17) ◽  
pp. 6272
Author(s):  
Evgeny P. Barykin ◽  
Aleksandra I. Garifulina ◽  
Anna P. Tolstova ◽  
Anastasia A. Anashkina ◽  
Alexei A. Adzhubei ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Cholinergic Neurons ◽  
Xenopus Laevis Oocytes ◽  
Aβ Peptide ◽  
Amino Acid Residues ◽  
Cholinergic Dysfunction ◽  
Potential Binding ◽  
Electrode Voltage ◽  
Potential Binding Site

The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the 11EVHH14 site in Aβ peptide mediates its interaction with α4β2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of Aβ-α4β2 nAChR complex is based on the interaction of 11EVHH14 with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a 35HAEE38 site in α4β2 nAChR, which is charge-complementary to 11EVHH14, and molecular modeling showed that a stable Aβ42-α4β2 nAChR complex could be formed via the 11EVHH14:35HAEE38 interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH2 can bind to Aβ via 11EVHH14 site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH2 tetrapeptide completely abolishes the Aβ42-induced inhibition of α4β2 nAChR. Thus, we suggest that 35HAEE38 is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH2 tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD.

scholarly journals A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

Marine Drugs ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 106 ◽  
Author(s):  
Hong Xing ◽  
Sunil Keshwah ◽  
Anne Rouchaud ◽  
William R. Kem
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Secondary Compounds ◽  
Piperidine Ring ◽  
Medical Disorders ◽  
In Vitro Investigation ◽  
Α7 Nachrs

Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

Aphicidal activity of imidacloprid against a tobacco feeding strain of Myzus persicae (Homoptera: Aphididae) from Japan closely related to Myzus nicotianae and highly resistant to carbamates and organophosphates

1996 ◽  
Vol 86 (2) ◽  
pp. 165-171 ◽  
Author(s):  
Ralf Nauen ◽  
Jürgen Strobel ◽  
Klaus Tietjen ◽  
Yuichi Otsu ◽  
Christoph Erdelen ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Myzus Persicae ◽  
Acetylcholine Receptors ◽  
Polyacrylamide Gel Electrophoresis ◽  
Susceptible Strain ◽  
Binding Assays ◽  
Organophosphate Insecticide ◽  
Japanese Strain ◽  
Myzus Nicotianae

AbstractWe investigated the resistance potential of a red-coloured Japanese strain (JR) of a tobacco feeding form of Myzus persicae (Sulzer) of the M. persicae species complex closely related to the tobacco aphid Myzus nicotianae Blackman. Bioassays were performed with a range of insecticides, imidacloprid, nicotine and cartap, thought to act on nicotinic acetylcholine receptors in vivo, as well as with two conventional insecticides, pirimicarb and oxydemeton-methyl, acting on acetylchol-inesterase (AChE). Compared to a susceptible strain, JR showed high resistance to pirimicarb and oxydemeton-methyl, but was far less resistant to nicotine, cartap and imidacloprid. Imidacloprid was, among the insecticides tested, the most active compound in contact and ingestion bioassays. Compared to the susceptible strain, JR showed four-to seven-fold resistance to imidacloprid depending on the type of bioassay. Resistance factors for other insecticides tested in an oral ingestion bioassay were: cartap five-fold, nicotine nine-fold, oxydemeton-methyl 107-fold and pirimicarb > 385-fold. JR showed high carboxylesterase activity. Polyacrylamide gel electrophoresis indicated esterase FE4 as the major carboxylesterase. As for most M. persicae strains and some Greek strains of M. nicotianae, JR was monomorphic for glutamate oxalacetate transaminase. Studies with pirimicarb showed a marked insensitivity of AChE to inhibition by this chemical, whilst such insensitivity could not be detected with the organophosphate insecticide oxydemeton-methyl. Receptor binding assays with [3H]-imidacloprid in aphid homogenates revealed I50-values of 0.4 to 0.8 nM and no statistical difference between the JR and susceptible strain.

scholarly journals Network meta-analysis: a comparison of effectiveness and safety of partial agonists of nicotinic acetylcholine receptors varenicline and cytisine for smoking cessation

2018 ◽  
Vol 16 (4) ◽  
pp. 19-32
Author(s):  
Elena V. Radchenko ◽  
Olga A. Sykhovskaya ◽  
Timofey L. Galankin ◽  
Aleksei S. Kolbin ◽  
Maria A. Smirnova
Keyword(s):  
Smoking Cessation ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Meta Analysis ◽  
Efficacy And Safety ◽  
Serious Adverse Events ◽  
Nicotinic Acetylcholine ◽  
Partial Agonists ◽  
Safety Parameters ◽  
Comparison Of Effectiveness

Background. Partial agonists of α4b2 nicotinic acetylcholine receptors are the most effective treatment strategy for tobacco smoking cessation. They are able to alleviate withdrawal symptoms and to reduce smoking satisfaction. The aim of this study was to review the efficacy and safety of nicotinic receptor partial agonists varenicline and cytisine, for smoking cessation. Methods. A search for randomized controlled trials was done using the terms (“cytisine”, “tabex”, “varenicline” or 'partial agonists of nicotinic receptors’) in MEDLINE, EMBASE, eLibrary in May 2018. Types of participants, the doses and duration of the treatments, efficacy and safety parameters, quality of randomization and blinding procedures were evaluated. Bayesian network meta-analysis was performed. Results. Cytisine overcame placebo in the 12, 24 and 52 weeks of therapy with the following odds ratios (ORs) for abstinence: 3.3 (95% CrI 1.8–5.8), 3.9 (2.4–6.7), 3.8 (CrI 1.3–11,9) accordingly. Varenicline in 2 mg/day dose overcame placebo in the 12, 24 and 52 weeks of therapy with the ORs: 4.0 (3.3–4.7), 3.1 (2.5–3.7), 2.9 (2.2–4.1) accor dingly. Varenicline in 1 mg/day dose overcame placebo in 12 and 52 weeks of therapy, the ORs were 3.0 (2.0–4.7) and 2.3 (1.3–4.4) accordingly. Varenicline in 0.5 mg/day dose overcame placebo in 12 weeks of therapy only with the OR 2.4 (1.3–4.4). Cytisine and varenicline 2 mg/day were associated with more gastrointestinal disturbances than placebo with the ORs 6.2 (2.1–22.8) and 2.4 (2.0–2.8) accordingly. Cytisine and varenicline 2 mg/day were associated with more psychiatric problems than placebo with ORs 5.2 (1.9–15.1) and 1.6 (1.3–1.9) accordingly. There was no difference in serious adverse events between the investigated drugs and placebo: OR for cytisine was 2.4 (0.8–6.8), varenicline 0.5 mg/day – 2.0 (0.5–6.6), varenicline 1.0 mg/day – 1.0 (0.3–2.7), varenicline 2 mg/day – 1.0 (0.7–1.4). Conclusion. Cytisine was proved to be as effective and safe aid for smoking cessation as varenicline.

scholarly journals Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity

2011 ◽  
Vol 4 (6) ◽  
pp. 822-847 ◽  
Author(s):  
David Pubill ◽  
Sara Garcia-Ratés ◽  
Jordi Camarasa ◽  
Elena Escubedo
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Ros Production ◽  
Monoamine Transporters ◽  
Neuronal Nicotinic Receptors ◽  
Abused Drugs ◽  
Amphetamine Derivatives

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found.

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