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Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 22667

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Dr. Dina Manetti

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Department of Neuroscience, Psychology, Drug Research and Child’s Health–Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy
Interests: drug discovery; medicinal chemistry; synthesis of heterocyclic compounds; structure–activity relationships

Special Issue Information

Dear Colleagues,

Nicotinic ligands are involved in many different physiological and pathological processes, as well as an important drug target for several conditions, and they represent a topic of intense interest in medicinal chemistry. A better understanding of the receptor pharmacology provides a deeper insight into the mechanism of ligand binding, and ligand selectivity and the discovery of compounds able to modulate nicotinic acetylcholine receptors are important for achieving subtype selectivity, for obtaining pharmacological tools, and for studying nicotinic receptors. This Special Issue welcomes original articles, reviews, and short communications on all aspects of nicotinic receptors, including structural and computational studies, drug design and medicinal chemistry, biochemical and pharmacological studies, and structure–activity relationships on synthetic and natural ligands (also snake and snail venoms) with distinct properties (agonists, antagonists, partial agonists, silent agonists, allosteric modulators and ligands acting at multiple targets).

Dr. Dina Manetti
Guest Editor

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Keywords

Nicotinic acetylcholine receptors
nAchR subtypes
Chemical synthesis
Pharmacological studies
Orthosteric ligands
Allosteric modulators

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Published Papers (6 papers)

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Research

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16 pages, 1557 KiB

Open AccessArticle

Effect of Intrahippocampal Administration of α7 Subtype Nicotinic Receptor Agonist PNU-282987 and Its Solvent Dimethyl Sulfoxide on the Efficiency of Hypoxic Preconditioning in Rats

by Elena I. Zakharova, Andrey T. Proshin, Mikhail Y. Monakov and Alexander M. Dudchenko

Molecules 2021, 26(23), 7387; https://doi.org/10.3390/molecules26237387 - 6 Dec 2021

Cited by 1 | Viewed by 1712

Abstract

We have previously suggested a key role of the hippocampus in the preconditioning action of moderate hypobaric hypoxia (HBH). The preconditioning efficiency of HBH is associated with acoustic startle prepulse inhibition (PPI). In rats with PPI > 40%, HBH activates the cholinergic projections of hippocampus, and PNU-282987, a selective agonist of α7 nicotinic receptors (α7nAChRs), reduces the HBH efficiency and potentiating effect on HBH of its solvent dimethyl sulfoxide (DMSO, anticholinesterase agent) when administered intraperitoneally. In order to validate the hippocampus as a key structure in the mechanism of hypoxic preconditioning and research a significance of α7nAChR activation in the hypoxic preconditioning, we performed an in vivo pharmacological study of intrahippocampal injections of PNU-282987 into the CA1 area on HBH efficiency in rats with PPI ≥ 40%. We found that PNU-282987 (30 μM) reduced HBH efficiency as with intraperitoneal administration, while DMSO (0.05%) still potentiated this effect. Thus, direct evidence of the key role of the hippocampus in the preconditioning effect of HBH and some details of this mechanism were obtained in rats with PPI ≥ 40%. The activation of α7nAChRs is not involved in the cholinergic signaling initiated by HBH or DMSO via any route of administration. Possible ways of the potentiating action of DMSO on HBH efficiency and its dependence on α7nAChRs are discussed. Full article

(This article belongs to the Special Issue Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances)

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19 pages, 4068 KiB

Open AccessArticle

[¹⁸F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson’s Disease

by Anthony-David T. Campoy, Christopher Liang, Reisha M. Ladwa, Krystal K. Patel, Ishani H. Patel and Jogeshwar Mukherjee

Molecules 2021, 26(23), 7360; https://doi.org/10.3390/molecules26237360 - 4 Dec 2021

Cited by 14 | Viewed by 2947

Abstract

We report [¹⁸F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson’s disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies. Because the small size of mice brain poses challenges for PET imaging, improved methods for radiosynthesis of [¹⁸F]nifene and simplified PET/CT procedures in mice were developed by comparing intravenous (IV) and intraperitoneal (IP) administered [¹⁸F]nifene. An optimal PET/CT imaging time of 30–60 min post injection of [¹⁸F]nifene was established to provide thalamus to cerebellum ratio of 2.5 (with IV) and 2 (with IP). Transgenic Hualpha-Syn(A53T) mice brain slices exhibited 20–35% decrease while in vivo a 20–30% decrease of [¹⁸F]nifene was observed. Lewy bodies and α-synuclein aggregates were confirmed in human PD brain sections which lowered the [¹⁸F]nifene binding by more than 50% in anterior cingulate. Thus [¹⁸F]nifene offers a valuable tool for PET imaging studies of PD. Full article

(This article belongs to the Special Issue Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances)

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11 pages, 3310 KiB

Open AccessArticle

The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, Schistocerca gregaria

by Victoria L. Luck, David P. Richards, Ashif Y. Shaikh, Henrik Franzyk and Ian R. Mellor

Molecules 2021, 26(22), 7007; https://doi.org/10.3390/molecules26227007 - 19 Nov 2021

Cited by 2 | Viewed by 2112

Abstract

Alterations in the polyamine and amino acid (tyrosine) moieties of philanthotoxin-343 (PhTX-343) were investigated for their effects on the antagonism of nicotinic acetylcholine receptors (nAChRs) isolated from the locust (Schistocerca gregaria) mushroom body. Through whole-cell patch-clamp recordings, the philanthotoxin analogues in this study were shown to cause inhibition of the inward current when co-applied with acetylcholine (ACh). PhTX-343 (IC₅₀ = 0.80 μM at −75 mV) antagonised locust nAChRs in a use-dependent manner, suggesting that it acts as an open-channel blocker. The analogue in which both the secondary amine functionalities were replaced with methylene groups (i.e., PhTX-12) was ~6-fold more potent (IC₅₀ (half-maximal inhibitory concentration) = 0.13 μM at −75 mV) than PhTX-343. The analogue containing cyclohexylalanine as a substitute for the tyrosine moiety of PhTX-343 (i.e., Cha-PhTX-343) was also more potent (IC₅₀ = 0.44 μM at −75 mV). A combination of both alterations to PhTX-343 generated the most potent analogue, i.e., Cha-PhTX-12 (IC₅₀ = 1.71 nM at −75 mV). Modulation by PhTX-343 and Cha-PhTX-343 fell into two distinct groups, indicating the presence of two pharmacologically distinct nAChR groups in the locust mushroom body. In the first group, all concentrations of PhTX-343 and Cha-PhTX-343 inhibited responses to ACh. In the second group, application of PhTX-343 or Cha-PhTX-343 at concentrations ≤100 nM caused potentiation, while concentrations ≥ 1 μM inhibited responses to ACh. Cha-PhTX-12 may have potential to be developed into insecticidal compounds with a novel mode of action. Full article

(This article belongs to the Special Issue Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances)

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16 pages, 5171 KiB

Open AccessArticle

Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

by Denis Kudryavtsev, Anastasia Isaeva, Daria Barkova, Ekaterina Spirova, Renata Mukhutdinova, Igor Kasheverov and Victor Tsetlin

Molecules 2021, 26(5), 1278; https://doi.org/10.3390/molecules26051278 - 26 Feb 2021

Cited by 2 | Viewed by 2202

Abstract

Slow-channel congenital myasthenic syndromes (SCCMSs) are rare genetic diseases caused by mutations in muscle nicotinic acetylcholine receptor (nAChR) subunits. Most of the known SCCMS-associated mutations localize at the transmembrane region near the ion pore. Only two SCCMS point mutations are at the extracellular domains near the acetylcholine binding site, α1(G153S) being one of them. In this work, a combination of molecular dynamics, targeted mutagenesis, fluorescent Ca²⁺ imaging and patch-clamp electrophysiology has been applied to G153S mutant muscle nAChR to investigate the role of hydrogen bonds formed by Ser 153 with C-loop residues near the acetylcholine-binding site. Introduction of L199T mutation to the C-loop in the vicinity of Ser 153 changed hydrogen bonds distribution, decreased acetylcholine potency (EC₅₀ 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca²⁺ rise (τ 14.2 ± 0.3 vs. 34.0 ± 0.4 s). These results shed light on molecular mechanisms of nAChR activation-desensitization and on the involvement of such mechanisms in channelopathy genesis. Full article

(This article belongs to the Special Issue Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances)

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Review

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17 pages, 1301 KiB

Open AccessReview

Nicotinic Acetylcholine Receptors in the Respiratory Tract

by Monika I. Hollenhorst and Gabriela Krasteva-Christ

Molecules 2021, 26(20), 6097; https://doi.org/10.3390/molecules26206097 - 9 Oct 2021

Cited by 24 | Viewed by 6334

Abstract

Nicotinic acetylcholine receptors (nAChR) are widely distributed in neuronal and non-neuronal tissues, where they play diverse physiological roles. In this review, we highlight the recent findings regarding the role of nAChR in the respiratory tract with a special focus on the involvement of nAChR in the regulation of multiple processes in health and disease. We discuss the role of nAChR in mucociliary clearance, inflammation, and infection and in airway diseases such as asthma, chronic obstructive pulmonary disease, and cancer. The subtype diversity of nAChR enables differential regulation, making them a suitable pharmaceutical target in many diseases. The stimulation of the α3β4 nAChR could be beneficial in diseases accompanied by impaired mucociliary clearance, and the anti-inflammatory effect due to an α7 nAChR stimulation could alleviate symptoms in diseases with chronic inflammation such as chronic obstructive pulmonary disease and asthma, while the inhibition of the α5 nAChR could potentially be applied in non-small cell lung cancer treatment. However, while clinical studies targeting nAChR in the airways are still lacking, we suggest that more detailed research into this topic and possible pharmaceutical applications could represent a valuable tool to alleviate the symptoms of diverse airway diseases. Full article

(This article belongs to the Special Issue Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances)

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21 pages, 2403 KiB

Open AccessReview

Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors?

by Hugo R. Arias, Katarzyna M. Targowska-Duda, Jesús García-Colunga and Marcelo O. Ortells

Molecules 2021, 26(8), 2149; https://doi.org/10.3390/molecules26082149 - 8 Apr 2021

Cited by 13 | Viewed by 6298

Abstract

It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce antidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although their amount is not altered, which is possibly caused by higher endogenous ACh levels, which consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged as possible targets for SSRIs. Studies on dorsal raphe nucleus serotoninergic neurons support the concept that SSRI-induced nAChR inhibition decreases the glutamatergic hyperstimulation observed in stress conditions, which compensates the excessive 5-HT overflow in these neurons and, consequently, ameliorates depression symptoms. At the molecular level, SSRIs inhibit different nAChR subtypes by noncompetitive mechanisms, including ion channel blockade and induction of receptor desensitization, whereas α9α10 nAChRs, which are peripherally expressed and not directly involved in depression, are inhibited by competitive mechanisms. According to the functional and structural results, SSRIs bind within the nAChR ion channel at high-affinity sites that are spread out between serine and valine rings. In conclusion, SSRI-induced inhibition of a variety of nAChRs expressed in different neurotransmitter systems widens the complexity by which these antidepressants may act clinically. Full article

(This article belongs to the Special Issue Nicotinic Receptors: Pharmacological Studies, Design and Synthesis of Pharmacologically Active Substances)

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