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Progress in the Treatment of CNS Disorders: From In Silico to In Vivo

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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 (30 April 2023) | Viewed by 7150

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Dr. Agnieszka A. Kaczor

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

Special Issue Information

Dear Colleagues,

Central nervous system (CNS) disorders, including mental and neurodegenerative diseases, affect millions of patients worldwide and are underlain by the chronic and progressive degradation of neural function. The current understanding of the pathomechanism of these complex and multi-factorial diseases is limited. Consequently, the available drugs are not able to stop the disease progression but to slow it down only. Novel compounds to treat CNS diseases are constantly being sought. It is facilitated by computer-aided approaches, such as construction of QSAR models, molecular docking, virtual screening, and molecular dynamics. However, any in silico predictions require experimental validation, in particular using in vitro and in vivo methods.

Current progress in the treatment of CNS diseases is limited by the fact that the pharmaceutical industry is highly cautious in 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. The efforts of academia in this field can accelerate the development of efficient CNS therapeutics.

In the light of above, in this Special Issue of Molecules we would like to illustrate progress in the discovery of CNS active compounds, starting from compound design, especially supported by molecular modeling techniques, through modern synthesis methods of novel chemical entities and their in vitro validation of behavioral studies in animal models.

Dr. Agnieszka A. Kaczor
Guest Editor

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Keywords

CNS agents
computer-aided drug design
behavioral studies
mental diseases
neurodegenerative diseases

Published Papers (5 papers)

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Research

15 pages, 8995 KiB

Open AccessArticle

Novel 1-(1-Arylimiazolin-2-Yl)-3-Arylalkilurea Derivatives with Modulatory Activity on Opioid MOP Receptors

by Dominik Straszak, Sylwia Woźniak, Agata Siwek, Monika Głuch-Lutwin, Marcin Kołaczkowski, Aldona Pietrzak, Bartłomiej Drop and Dariusz Matosiuk

Molecules 2024, 29(3), 571; https://doi.org/10.3390/molecules29030571 - 24 Jan 2024

Viewed by 837

Abstract

μ-opioid receptor ligands such as morphine and fentanyl are the most known and potent painkillers. However, the severe side effects seen with their use significantly limit their widespread use. The continuous broadening of knowledge about the properties of the interactions of the MOP receptor (human mu opioid receptor, OP3) with ligands and specific intracellular signaling pathways allows for the designation of new directions of research with respect to compounds with analgesic effects in a mechanism different from classical ligands. Allosteric modulation is an extremely promising line of research. Compounds with modulator properties may provide a safer alternative to the currently used opioids. The aim of our research was to obtain a series of urea derivatives of 1-aryl-2-aminoimidazoline and to determine their activity, mechanism of biological action and selectivity toward the MOP receptor. The obtained compounds were subjected to functional tests (cAMP accumulation and β-arrestin recruitment) in vitro. One of the obtained compounds, when administered alone, did not show any biological activity, while when co-administered with DAMGO, it inhibited β-arrestin recruitment. These results indicate that this compound is a negative allosteric modulator (NAM) of the human MOP receptor. Full article

(This article belongs to the Special Issue Progress in the Treatment of CNS Disorders: From In Silico to In Vivo)

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14 pages, 3695 KiB

Open AccessArticle

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives

by Kinga Paruch, Barbara Kaproń, Jarogniew J. Łuszczki, Agata Paneth and Tomasz Plech

Molecules 2023, 28(13), 5287; https://doi.org/10.3390/molecules28135287 - 07 Jul 2023

Cited by 2 | Viewed by 1019

Abstract

The main aim of the current project was to investigate the effect of the linker size in 4-alkyl-5-aryl-1,2,4-triazole-3-thione derivatives, known as a group of antiepileptic drug candidates, on their affinity towards voltage-gated sodium channels (VGSCs). The rationale of the study was based both on the SAR observations and docking simulations of the interactions between the designed ligands and the binding site of human VGSC. HYDE docking scores, which describe hydrogen bonding, desolvation, and hydrophobic effects, obtained for 5-[(3-chlorophenyl)ethyl]-4-butyl/hexyl-1,2,4-triazole-3-thiones, justified their beneficial sodium channel blocking activity. The results of docking simulations were verified using a radioligand binding assay with [³H]batrachotoxin. Unexpectedly, although the investigated triazole-based compounds acted as VGSC ligands, their affinities were lower than those of the respective analogs containing shorter alkyl linkers. Since numerous sodium channel blockers are recognized as antiepileptic agents, the obtained 1,2,4-triazole derivatives were examined for antiepileptic potential using an experimental model of tonic–clonic seizures in mice. Median effective doses (ED₅₀) of the compounds examined in MES test reached 96.6 ± 14.8 mg/kg, while their median toxic doses (TD₅₀), obtained in the rotarod test, were even as high as 710.5 ± 47.4 mg/kg. Full article

(This article belongs to the Special Issue Progress in the Treatment of CNS Disorders: From In Silico to In Vivo)

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28 pages, 8306 KiB

Open AccessArticle

Development and Characterization of Novel Selective, Non-Basic Dopamine D₂ Receptor Antagonists for the Treatment of Schizophrenia

by Piotr Stępnicki, Sylwia Wośko, Agata Bartyzel, Agata Zięba, Damian Bartuzi, Klaudia Szałaj, Tomasz M. Wróbel, Emilia Fornal, Jens Carlsson, Ewa Kędzierska, Ewa Poleszak, Marián Castro and Agnieszka A. Kaczor

Molecules 2023, 28(10), 4211; https://doi.org/10.3390/molecules28104211 - 20 May 2023

Viewed by 2075

Abstract

The dopamine D₂ receptor, which belongs to the family of G protein-coupled receptors (GPCR), is an important and well-validated drug target in the field of medicinal chemistry due to its wide distribution, particularly in the central nervous system, and involvement in the pathomechanism of many disorders thereof. Schizophrenia is one of the most frequent diseases associated with disorders in dopaminergic neurotransmission, and in which the D₂ receptor is the main target for the drugs used. In this work, we aimed at discovering new selective D₂ receptor antagonists with potential antipsychotic activity. Twenty-three compounds were synthesized, based on the scaffold represented by the D2AAK2 compound, which was discovered by our group. This compound is an interesting example of a D₂ receptor ligand because of its non-classical binding to this target. Radioligand binding assays and SAR analysis indicated structural modifications of D2AAK2 that are possible to maintain its activity. These findings were further rationalized using molecular modeling. Three active derivatives were identified as D₂ receptor antagonists in cAMP signaling assays, and the selected most active compound 17 was subjected to X-ray studies to investigate its stable conformation in the solid state. Finally, effects of 17 assessed in animal models confirmed its antipsychotic activity in vivo. Full article

(This article belongs to the Special Issue Progress in the Treatment of CNS Disorders: From In Silico to In Vivo)

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25 pages, 11579 KiB

Open AccessArticle

Trisubstituted 1,3,5-Triazines as Histamine H₄ Receptor Antagonists with Promising Activity In Vivo

by Agnieszka Olejarz-Maciej, Szczepan Mogilski, Tadeusz Karcz, Tobias Werner, Katarzyna Kamińska, Jarosław Kupczyk, Ewelina Honkisz-Orzechowska, Gniewomir Latacz, Holger Stark, Katarzyna Kieć-Kononowicz and Dorota Łażewska

Molecules 2023, 28(10), 4199; https://doi.org/10.3390/molecules28104199 - 19 May 2023

Viewed by 1262

Abstract

Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H₄ receptor (H₄R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H₄R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H₄R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H₄R. The majority of compounds showed a moderate affinity for this receptor (K_i > 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound 6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; K_i = 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; P_e = 12.26 × 10⁻⁶ cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound 6 tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound 6 at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound 6 is a promising ligand for further studies. Full article

(This article belongs to the Special Issue Progress in the Treatment of CNS Disorders: From In Silico to In Vivo)

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13 pages, 7816 KiB

Open AccessFeature PaperArticle

Bio-Computational Evaluation of Compounds of Bacopa Monnieri as a Potential Treatment for Schizophrenia

by Ali H. Alharbi

Molecules 2022, 27(20), 7050; https://doi.org/10.3390/molecules27207050 - 19 Oct 2022

Cited by 2 | Viewed by 1443

Abstract

Schizophrenia is a horrible mental disorder characterized by distorted perceptions of reality. Investigations have not identified a single etiology for schizophrenia, and there are multiple hypotheses based on various aspects of the disease. There is no specific treatment for schizophrenia. Hence, we have tried to investigate the updated information stored in the genetic databases related to genes that could be responsible for schizophrenia and other related neuronal disorders. After implementing combined computational methodology, such as protein-protein interaction analysis led by system biology approach, in silico docking analysis was performed to explore the 3D binding pattern of Bacopa monnieri natural compounds while interacting with STXBP1. The best-identified compound was CID:5319292 based on −10.3 kcal/mol binding energy. Further, selected complexes were dynamically evaluated by MDS methods, and the output reveals that the STXBP1-CID:5281800 complex showed the lowest RMSD value, i.e., between 0.3 and 0.4 nm. Hence, identified compounds could be used to develop and treat neuronal disorders after in vivo/in vitro testing. Full article

(This article belongs to the Special Issue Progress in the Treatment of CNS Disorders: From In Silico to In Vivo)

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