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Special Issue "20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease"

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 15 March 2024 | Viewed by 1699

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Special Issue Editors

Dr. Elena Cichero

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Guest Editor

Department of Pharmacy, University of Genoa, Viale Benedetto XV, 16132 Genoa, Italy
Interests: medicinal chemistry; drug design; GPCR; enzyme; neuroprotective agents, cystic fibrosis; QSAR; virtual screening; homology modeling
Special Issues, Collections and Topics in MDPI journals

Dr. Michele Tonelli

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Guest Editor

Department of Pharmacy, University of Genoa Viale Benedetto XV, 3, 16132 Genoa, Italy
Interests: medicinal chemistry; neuroprotective drugs; anti-Alzheimer’s drug; multitarget-directed ligands; antiviral drugs; antiprotozoan drugs

Special Issue Information

Dear Colleagues,

Nowadays, human life expectancy is increasing, thus leading to population aging being inevitable and often accompanied by increased levels of patients developing neurodegenerative diseases. Neuroprotection represents an intriguing strategic approach to contrast neurodegeneration as shown in a variety of central nervous system (CNS) disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and drug misuse-induced neurotoxicity, among others. Recently, novel therapeutic agents for neurodegenerative diseases based on small molecules as well as unprecedented druggable targets mediating a neuroprotective effect have been investigated. This Special Issue invites both reviews and original articles that shed light on the state of the art and on the latest findings in the search for novel drug-like neuroprotective agents, and aims to elucidate future directions probing promising biological targets such as GPCRs or enzymes. The rational design and development of new neuroprotective compounds based on virtual screening applications and high-throughput screening (HTS) campaigns are also included in the scope of this Special Issue.

Dr. Elena Cichero
Dr. Michele Tonelli
Guest Editors

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

neurodegeneration
neuroprotective agents
chemical synthesis
drug design
GPCR
enzyme
screening

Published Papers (3 papers)

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Research

27 pages, 6281 KiB

Open AccessArticle

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

and

Pharmaceuticals 2023, 16(11), 1632; https://doi.org/10.3390/ph16111632 - 20 Nov 2023

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Abstract

Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative–structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α₂-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α₂-ADR putative selectivity. These computational methods allowed the identification of the α₂A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α₂-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation. Full article

(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)

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14 pages, 2095 KiB

Open AccessArticle

Distinct and Dynamic Changes in the Temporal Profiles of Neurotransmitters in Drosophila melanogaster Brain following Volatilized Cocaine or Methamphetamine Administrations

Ana Filošević Vujnović

Lara Saftić Martinović

Marta Medija

and

Rozi Andretić Waldowski

Pharmaceuticals 2023, 16(10), 1489; https://doi.org/10.3390/ph16101489 - 19 Oct 2023

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Abstract

Due to similarities in genetics, cellular response, and behavior, Drosophila is used as a model organism in addiction research. A well-described behavioral response examined in flies is the induced increase in locomotor activity after a single dose of volatilized cocaine (vCOC) and volatilized methamphetamine (vMETH), the sensitivity, and the escalation of the locomotor response after the repeated dose, the locomotor sensitization. However, knowledge about how vCOC and vMETH affect different neurotransmitter systems over time is scarce. We used LC-MS/MS to systematically examine changes in the concentration of neurotransmitters, metabolites and non-metabolized COC and METH in the whole head homogenates of male flies one to seven hours after single and double vCOC or vMETH administrations. vMETH leads to complex changes in the levels of examined substances over time, while vCOC strongly and briefly increases concentrations of dopamine, tyramine and octopamine followed by a delayed degradation into N-acetyl dopamine and N-acetyl tyramine. The first exposure to psychostimulants leads to significant and dynamic changes in the concentrations relative to the second administration when they are more stable over several hours. Further investigations are needed to understand neurochemical and molecular changes post-psychostimulant administration. Full article

(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)

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18 pages, 4366 KiB

Open AccessArticle

Vitamin E and Silymarin Reduce Oxidative Tissue Damage during Gentamycin-Induced Nephrotoxicity

and

Pharmaceuticals 2023, 16(10), 1365; https://doi.org/10.3390/ph16101365 - 27 Sep 2023

Viewed by 576

Abstract

Aminoglycoside antibiotics and gentamicin (GN), in particular, are still widely used in clinical practice. It is a well-known fact that GN causes nephrotoxicity, and redox disturbances are discussed as a factor in its side effects. Recently, a new type of cell oxidative death, named ferroptosis, was discovered; it is associated with iron accumulation in the cell, glutathione (GSH) depletion and inactivation of glutathione peroxidase-4 (GPX4), reactive oxygen species (ROS) increment with concomitant lipid peroxidation. In this regard, a possible connection between GN-induced renal damage, ferroptosis and the overall antioxidant status of the organism could be investigated. Moreover, due to its beneficial effects, GN is still one of the main choices as a therapeutic agent for several diseases, and the possible reduction of its side effects with the application of certain antioxidants will be of important clinical significance. The study was conducted with adult male white mice divided into several groups (n = 6). GN nephrotoxicity was induced by the administration of GN 100–200 mg/kg i.p. for 10 days. The control group received only saline. The other groups received either Vitamin E (400 mg/kg p.o.) or Silymarin (200 mg/kg p.o.) applied alone or together with GN for the same period. After the end of the study, the animals were sacrificed, and blood and tissue samples were taken for the assessment of biochemical parameters and antioxidant status, as well as routine and specific for GPX4 histochemistry examination. The experimental results indicate that GN-induced nephrotoxicity negatively modulates GPX4 activity and is associated with increased production of ROS and lipid peroxidation. The groups treated with antioxidants demonstrated preserved antioxidant status and better GPX4 activity. In conclusion, the inhibition of ROS production and especially the suppression of ferroptosis, could be of clinical potential and can be applied as a means of reducing the toxic effects of GN application. Full article

(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease)

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Special Issue "20th Anniversary of Pharmaceuticals–Drug Design and Pharmacological Advances in Neurodegenerative Disease"

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