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 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.

Nicotinic acetylcholine receptors: α-conotoxins as templates for rational drug design

2003 ◽  
Vol 31 (3) ◽  
pp. 634-636 ◽  
Author(s):  
Robert W. Janes
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Docking Studies ◽  
Rational Drug Design ◽  
Synaptic Membranes ◽  
Nicotinic Acetylcholine ◽  
Computational Docking ◽  
Acetylcholine Binding Protein ◽  
Topological Features

Nicotinic acetylcholine receptors (nAChRs) mediate the passage of potassium and sodium ions across synaptic membranes. Two classes of receptors exist: the neuromuscular nAChRs, which mediate signals between nerve and muscle cells, and the neuronal nAChRs, which are found throughout the nervous system. For treatment of diseases involving nAChRs, drugs must be designed with a high level of selectivity towards only one of these classes or subclasses (in the case of neuronal receptors). α-Conotoxins, small polypeptides isolated from the venoms of marine snails, represent molecules with just this type of selectivity, with specificity even towards certain subclasses of nAChRs. The availability of high-resolution crystal structures of α-conotoxins provides the opportunity to examine the structural features that orchestrate their preferential blocking action. In the present study of a neuromuscular- and a neuronal-specific α-conotoxin, SI and EpI respectively, important and significant differences can be seen in the shapes of the molecules, which must reflect topological features of the different types of target receptor subunits. These then provide a template for computational docking studies with the homologous acetylcholine-binding protein, whose structure is known, so drug analogues of the naturally occurring toxins can be developed with the desired specificities.

scholarly journals Identifying the Binding Site of Novel Methyllycaconitine (MLA) Analogs at α4β2 Nicotinic Acetylcholine Receptors

2010 ◽  
Vol 1 (12) ◽  
pp. 796-809 ◽  
Author(s):  
Gracia X. J. Quek ◽  
Diana Lin ◽  
Jill I. Halliday ◽  
Nathan Absalom ◽  
Joseph I. Ambrus ◽  
...  
Keyword(s):  
Binding Site ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine

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.

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