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Molecules
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Recent Advances in the Modulation of Cholinergic Signaling II
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Recent Advances in the Modulation of Cholinergic Signaling II

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

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 10737

Special Issue Editor

Prof. Dr. Clelia Dallanoce

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Milan, Via Luigi Mangiagalli 25, 20133 Milan, Italy
Interests: rational drug design; organic synthesis; structure-activity relationships; nicotinic acetylcholine receptors; muscarinic acetylcholine receptors; cholinesterase inhibitors; bifunctional and bitopic ligands
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is with great pleasure that I invite you to contribute to the Special Issue “Recent Advances in the Modulation of Cholinergic Signaling II,” which will mainly focus on new bioactive compounds capable of regulating cholinergic transmission in neuronal and non-neuronal tissues. Since acetylcholine-related functions are impaired in several disorders and pathological conditions, different pharmacological approaches have been explored in the context of innovative therapeutic applications. Additional mechanisms of action and/or downstream responses have more recently been associated with receptor targets of the cholinergic system, i.e., nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs), notably allosteric modulation (for both receptor families), biased signaling (for mAChRs), or silent agonism (for nAChRs). Overall, this evidence may enrich the repertoire of therapeutic opportunities for cholinergic ligands, including antitumor, anti-inflammatory, and analgesic activities. On the other hand, molecular fragments of cholinesterase (AChE and BChE) inhibitors are quite frequently incorporated in the structure of various hybrid ligands characterized by a dual or multitarget pharmacological profile, an approach aimed at improving their action on CNS disorders.

Contributions to this Special Issue, in the form of original research articles and short communications, may cover multidisciplinary aspects of the design, synthesis, and biological evaluation of novel small molecules affecting cholinergic neurotransmission, as well as their therapeutic potential.

Prof. Dr. Clelia Dallanoce
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design
  • organic synthesis
  • biological activity
  • In silico studies
  • nicotinic acetylcholine receptors
  • muscarinic acetylcholine receptors
  • cholinesterase inhibitors
  • allosteric modulators
  • dual-acting ligands
  • therapeutic applications

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Published Papers (4 papers)

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Research

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24 pages, 3620 KiB  
Article
Novel Xanomeline-Containing Bitopic Ligands of Muscarinic Acetylcholine Receptors: Design, Synthesis and FRET Investigation
by Carlo Matera, Michael Kauk, Davide Cirillo, Marco Maspero, Claudio Papotto, Daniela Volpato, Ulrike Holzgrabe, Marco De Amici, Carsten Hoffmann and Clelia Dallanoce
Molecules 2023, 28(5), 2407; https://doi.org/10.3390/molecules28052407 - 6 Mar 2023
Cited by 1 | Viewed by 2513
Abstract
In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection [...] Read more.
In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection of different kinetics and distinguishing between partial, full, and super agonism. Herein, we report the synthesis of the two series of bitopic ligands, 12-Cn and 13-Cn, and their pharmacological investigation at the M1, M2, M4, and M5 FRET-based receptor sensors. The hybrids were prepared by merging the pharmacophoric moieties of the M1/M4-preferring orthosteric agonist Xanomeline 10 and the M1-selective positive allosteric modulator 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) 11. The two pharmacophores were connected through alkylene chains of different lengths (C3, C5, C7, and C9). Analyzing the FRET responses, the tertiary amine compounds 12-C5, 12-C7, and 12-C9 evidenced a selective activation of M1 mAChRs, while the methyl tetrahydropyridinium salts 13-C5, 13-C7, and 13-C9 showed a degree of selectivity for M1 and M4 mAChRs. Moreover, whereas hybrids 12-Cn showed an almost linear response at the M1 subtype, hybrids 13-Cn evidenced a bell-shaped activation response. This different activation pattern suggests that the positive charge anchoring the compound 13-Cn to the orthosteric site ensues a degree of receptor activation depending on the linker length, which induces a graded conformational interference with the binding pocket closure. These bitopic derivatives represent novel pharmacological tools for a better understanding of ligand-receptor interactions at a molecular level. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling II)
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21 pages, 5313 KiB  
Article
Novel Uracil-Based Inhibitors of Acetylcholinesterase with Potency for Treating Memory Impairment in an Animal Model of Alzheimer’s Disease
by Vyacheslav E. Semenov, Irina V. Zueva, Sofya V. Lushchekina, Eduard G. Suleimanov, Liliya M. Gubaidullina, Marina M. Shulaeva, Oksana A. Lenina and Konstantin A. Petrov
Molecules 2022, 27(22), 7855; https://doi.org/10.3390/molecules27227855 - 14 Nov 2022
Cited by 4 | Viewed by 1694
Abstract
Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to [...] Read more.
Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to hexamethylene chains and quaternary ammonium groups; varying substituents (ester, salt, acid) at benzene ring were introduced into the chains and benzoate moieties. In vivo biological experiments demonstrated the potency of these compounds in decreasing the number of β-amyloid plaques and their suitability for the treatment of memory impairment in a transgenic model of Alzheimer’s disease. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling II)
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Graphical abstract

9 pages, 1140 KiB  
Communication
PyPLIF HIPPOS and Receptor Ensemble Docking Increase the Prediction Accuracy of the Structure-Based Virtual Screening Protocol Targeting Acetylcholinesterase
by Enade P. Istyastono, Florentinus Dika Octa Riswanto, Nunung Yuniarti, Vivitri D. Prasasty and Sudi Mungkasi
Molecules 2022, 27(17), 5661; https://doi.org/10.3390/molecules27175661 - 2 Sep 2022
Cited by 4 | Viewed by 1806
Abstract
In this article, the upgrading process of the structure-based virtual screening (SBVS) protocol targeting acetylcholinesterase (AChE) previously published in 2017 is presented. The upgraded version of PyPLIF called PyPLIF HIPPOS and the receptor ensemble docking (RED) method using AutoDock Vina were employed to [...] Read more.
In this article, the upgrading process of the structure-based virtual screening (SBVS) protocol targeting acetylcholinesterase (AChE) previously published in 2017 is presented. The upgraded version of PyPLIF called PyPLIF HIPPOS and the receptor ensemble docking (RED) method using AutoDock Vina were employed to calculate the ensemble protein–ligand interaction fingerprints (ensPLIF) in a retrospective SBVS campaign targeting AChE. A machine learning technique called recursive partitioning and regression trees (RPART) was then used to optimize the prediction accuracy of the protocol by using the ensPLIF values as the descriptors. The best protocol resulting from this research outperformed the previously published SBVS protocol targeting AChE. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling II)
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Review

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24 pages, 5579 KiB  
Review
Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators
by Dina Manetti, Silvia Dei, Hugo R. Arias, Laura Braconi, Alessio Gabellini, Elisabetta Teodori and Maria Novella Romanelli
Molecules 2023, 28(3), 1270; https://doi.org/10.3390/molecules28031270 - 28 Jan 2023
Cited by 14 | Viewed by 4139
Abstract
Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on [...] Read more.
Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4β2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the design of selective modulators. Experimental evidence supports the use of allosteric modulators as therapeutic tools for neurological and non-neurological conditions. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling II)
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