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Targeting Signaling Complexity of GPCRs for the Treatment of CNS Diseases

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 8898

Special Issue Editor

Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, PL-20093 Lublin, Poland
Interests: computer-aided drug design; medicinal chemistry; molecular modeling; CNS agents; GPCRs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Central nervous system (CNS) diseases are ranked as the leading cause of disability and comprise 16.8% of global deaths, and they have social and economic implications. Thus, it is not surprising that CNS disorders belong to the most costly medical conditions and are among the leading public health problems worldwide. Unfortunately, the pharmaceutical industry is highly cautious when it comes to investing in CNS drug development as it can cost billions more than any other therapeutic area yet has a 45% higher chance of failure than the drugs targeting other disorders.

Recent progress in the field of G protein-coupled receptors (GPCRs) which are drug targets for about 30% of drugs present on the market opens new possibilities to develop modern drugs for CNS diseases. The classical model of GPCR signaling involves action of one orthosteric ligand on one receptor which translates into the activation of a specific G protein that, in turn, is able to initiate particular signaling cascades. A growing body of evidence indicates, however, that GPCRs can be modulated in a much more complicated manner. Thus, we observe a paradigm change in GPCR-oriented drug discovery: classical orthosteric ligands are complemented with allosteric modulators, biased ligands, multitarget compounds, and dimer-specific ligands. Some of the recently reported CNS active compounds targeting novel GPCR signaling mechanisms have already been successfully tested in clinical studies. Among them is oliceridine (TRV130), a biased ligand of µ opioid receptor which was recently approved by the FDA for the management of acute pain that is severe enough to require an IV opioid analgesic.

In the light of the above, in this Special Issue of Molecules, we would like to illustrate the progress in the discovery of CNS active compounds targeting novel GPCR signaling mechanisms in silico studies and elaboration of new compounds.

Prof. Dr. Agnieszka A. Kaczor
Guest Editor

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Keywords

  • Allosteric modulators
  • Biased ligands
  • CNS diseases
  • GPCRs
  • Multi-target ligands

Published Papers (5 papers)

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Research

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39 pages, 14786 KiB  
Article
Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus
by Rosa Sparaco, Ewa Kędzierska, Agnieszka A. Kaczor, Anna Bielenica, Elisa Magli, Beatrice Severino, Angela Corvino, Ewa Gibuła-Tarłowska, Jolanta H. Kotlińska, Giorgia Andreozzi, Paolo Luciano, Elisa Perissutti, Francesco Frecentese, Marcello Casertano, Anna Leśniak, Magdalena Bujalska-Zadrożny, Małgorzata Oziębło, Raffaele Capasso, Vincenzo Santagada, Giuseppe Caliendo and Ferdinando Fiorinoadd Show full author list remove Hide full author list
Molecules 2022, 27(19), 6492; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27196492 - 01 Oct 2022
Cited by 4 | Viewed by 1527
Abstract
A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands [...] Read more.
A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study. Full article
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12 pages, 3145 KiB  
Article
Screening and Structure–Activity Relationship of D2AAK1 Derivatives for Potential Application in the Treatment of Neurodegenerative Diseases
by Oliwia Koszła, Przemysław Sołek, Piotr Stępnicki and Agnieszka A. Kaczor
Molecules 2022, 27(7), 2239; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072239 - 30 Mar 2022
Cited by 1 | Viewed by 1209
Abstract
Neurodegenerative and mental diseases are serious medical, economic and social problems. Neurodegeneration is referred to as a pathological condition associated with damage to nerve cells leading to their death. Treatment of neurodegenerative diseases is at present symptomatic only, and novel drugs are urgently [...] Read more.
Neurodegenerative and mental diseases are serious medical, economic and social problems. Neurodegeneration is referred to as a pathological condition associated with damage to nerve cells leading to their death. Treatment of neurodegenerative diseases is at present symptomatic only, and novel drugs are urgently needed which would be able to stop disease progression. We performed screening of reactive oxygen species, reactive nitrogen species, glutathione and level intracellular Ca2+. The studies were assessed using one-way ANOVA of variance with Dunnett’s post hoc test. Previously, we reported D2AAK1 as a promising compound for the treatment of neurodegenerative and mental disorders. Here, we show a screening of D2AAK1 derivatives aimed at the selection of the compound with the most favorable pharmacological profile. Selected compounds cause an increase in the proliferation of a hippocampal neuron-like cell line, changes in the levels of reactive oxygen and nitrogen forms, reduced glutathione and a reduced intracellular calcium pool. Upon analyzing the structure–activity relationship, we selected the compound with the most favorable profile for a neuroprotective activity for potential application in the treatment of neurodegenerative diseases. Full article
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14 pages, 2732 KiB  
Article
The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor—In Silico Study
by Justyna Żuk, Damian Bartuzi, Przemysław Miszta and Agnieszka A. Kaczor
Molecules 2022, 27(4), 1335; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27041335 - 16 Feb 2022
Cited by 5 | Viewed by 1696
Abstract
The dopamine D2 receptor, belonging to the class A G protein-coupled receptors (GPCRs), is an important drug target for several diseases, including schizophrenia and Parkinson’s disease. The D2 receptor can be activated by the natural neurotransmitter dopamine or by synthetic ligands, [...] Read more.
The dopamine D2 receptor, belonging to the class A G protein-coupled receptors (GPCRs), is an important drug target for several diseases, including schizophrenia and Parkinson’s disease. The D2 receptor can be activated by the natural neurotransmitter dopamine or by synthetic ligands, which in both cases leads to the receptor coupling with a G protein. In addition to receptor modulation by orthosteric or allosteric ligands, it has been shown that lipids may affect the behaviour of membrane proteins. We constructed a model of a D2 receptor with a long intracellular loop (ICL3) coupled with Giα1 or Giα2 proteins, embedded in a complex asymmetric membrane, and simulated it in complex with positive, negative or neutral allosteric ligands. In this study, we focused on the influence of ligand binding and G protein coupling on the membrane–receptor interactions. We show that there is a noticeable interplay between the cell membrane, G proteins, D2 receptor and its modulators. Full article
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18 pages, 6557 KiB  
Article
Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity
by Dorota Łażewska, Paula Zaręba, Justyna Godyń, Agata Doroz-Płonka, Annika Frank, David Reiner-Link, Marek Bajda, Dorota Stary, Szczepan Mogilski, Agnieszka Olejarz-Maciej, Maria Kaleta, Holger Stark, Barbara Malawska and Katarzyna Kieć-Kononowicz
Molecules 2021, 26(12), 3580; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26123580 - 11 Jun 2021
Cited by 3 | Viewed by 2121
Abstract
Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a [...] Read more.
Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents. Full article
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Review

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10 pages, 1396 KiB  
Review
Cebranopadol as a Novel Promising Agent for the Treatment of Pain
by Wojciech Ziemichod, Jolanta Kotlinska, Ewa Gibula-Tarlowska, Natalia Karkoszka and Ewa Kedzierska
Molecules 2022, 27(13), 3987; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27133987 - 21 Jun 2022
Cited by 5 | Viewed by 1730
Abstract
Opioids are used to treat pain, but despite their effectiveness, they possess several side effects such as respiratory depression, tolerance and physical dependence. Cebranopadol has been evaluated as a solution to this problem. The compound acts on the mu opioid receptor and the [...] Read more.
Opioids are used to treat pain, but despite their effectiveness, they possess several side effects such as respiratory depression, tolerance and physical dependence. Cebranopadol has been evaluated as a solution to this problem. The compound acts on the mu opioid receptor and the nociceptin/orphanin receptor and these receptors co-activation can reduce opioid side-effects without compromising analgesia. In the present review, we have compiled information on the effects of cebranopadol, its pharmacokinetics, and clinical trials involving cebranopadol, to further explore its promise in pain management. Full article
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