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Biomolecules
Special Issues
Recent Advances in Central Nervous System Drug Discovery
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Recent Advances in Central Nervous System Drug Discovery

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Structure and Dynamics".

Deadline for manuscript submissions: closed (10 July 2023) | Viewed by 21228

Special Issue Editor

Dr. Christopher L. Cioffi

E-Mail Website
Guest Editor
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Interests: central nervous system; small molecule drug discovery; structure- and ligand-based drug design; synthesis of molecular probes

Special Issue Information

Dear Colleagues,

Neurological disorders significantly outnumber diseases in other therapeutic areas. Experimental neuroscience in recent years has brought to light numerous exciting technologies, discoveries of new therapeutic interventions, and molecular targets of CNS disorders. However, developing drugs for central nervous system (CNS) disorders remains the most challenging area in drug discovery, including an incomplete understanding of the biology of multifaceted CNS conditions, such as Alzheimer's disease, the presence of a blood–brain barrier that restricts the flow of molecules to the brain, and a lack of clinically relevant animal models in which to test new drugs.

This Special Issue will gather discoveries of the current technologies, approaches and concepts in drug discovery for a full spectrum of disorders of the central nervous system, including but not limited to Alzheimer’s disease, Parkinson’s disease, Huntington disease, depression, anxiety, autism spectrum disorders, seizures, and strokes. Short and comprehensive research papers including the discovery and development of new effective drugs targeting the central nervous system (CNS) are welcome.

Dr. Christopher L. Cioffi
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. Biomolecules 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 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

  • neurodegeneration
  • neurotransmission
  • neuroinflammation
  • drug discovery
  • drug design

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Published Papers (6 papers)

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Research

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28 pages, 5227 KiB  
Article
New Multifunctional Agents for Potential Alzheimer’s Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones
by Natalia A. Elkina, Maria V. Grishchenko, Evgeny V. Shchegolkov, Galina F. Makhaeva, Nadezhda V. Kovaleva, Elena V. Rudakova, Natalia P. Boltneva, Sofya V. Lushchekina, Tatiana Y. Astakhova, Eugene V. Radchenko, Vladimir A. Palyulin, Ekaterina F. Zhilina, Anastasiya N. Perminova, Luka S. Lapshin, Yanina V. Burgart, Victor I. Saloutin and Rudy J. Richardson
Biomolecules 2022, 12(11), 1551; https://doi.org/10.3390/biom12111551 - 24 Oct 2022
Cited by 6 | Viewed by 2345
Abstract
Alzheimer’s disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and [...] Read more.
Alzheimer’s disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24–0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036–0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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18 pages, 3216 KiB  
Article
Design, Synthesis and Pharmacological Evaluation of Novel Conformationally Restricted N-arylpiperazine Derivatives Characterized as D2/D3 Receptor Ligands, Candidates for the Treatment of Neurodegenerative Diseases
by Thayssa Tavares da Silva Cunha, Rafaela Ribeiro Silva, Daniel Alencar Rodrigues, Pedro de Sena Murteira Pinheiro, Thales Kronenberger, Carlos Maurício R. Sant’Anna, François Noël and Carlos Alberto Manssour Fraga
Biomolecules 2022, 12(8), 1112; https://doi.org/10.3390/biom12081112 - 12 Aug 2022
Cited by 2 | Viewed by 2055
Abstract
Most neurodegenerative diseases are multifactorial, and the discovery of several molecular mechanisms related to their pathogenesis is constantly advancing. Dopamine and dopaminergic receptor subtypes are involved in the pathophysiology of several neurological disorders, such as schizophrenia, depression and drug addiction. For this reason, [...] Read more.
Most neurodegenerative diseases are multifactorial, and the discovery of several molecular mechanisms related to their pathogenesis is constantly advancing. Dopamine and dopaminergic receptor subtypes are involved in the pathophysiology of several neurological disorders, such as schizophrenia, depression and drug addiction. For this reason, the dopaminergic system and dopamine receptor ligands play a key role in the treatment of such disorders. In this context, a novel series of conformationally restricted N-arylpiperazine derivatives (5a–f) with a good affinity for D2/D3 dopamine receptors is reported herein. Compounds were designed as interphenylene analogs of the drugs aripiprazole (2) and cariprazine (3), presenting a 1,3-benzodioxolyl subunit as a ligand of the secondary binding site of these receptors. The six new N-arylpiperazine compounds were synthesized in good yields by using classical methodologies, and binding and guanosine triphosphate (GTP)-shift studies were performed. Affinity values below 1 μM for both target receptors and distinct profiles of intrinsic efficacy were found. Docking studies revealed that Compounds 5a–f present a different binding mode with dopamine D2 and D3 receptors, mainly as a consequence of the conformational restriction imposed on the flexible spacer groups of 2 and 3. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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Review

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23 pages, 7179 KiB  
Review
Central Nervous System Targeted Protein Degraders
by Bedwyr ab Ion Thomas, H. Lois Lewis, D. Heulyn Jones and Simon E. Ward
Biomolecules 2023, 13(8), 1164; https://doi.org/10.3390/biom13081164 - 25 Jul 2023
Cited by 6 | Viewed by 3638
Abstract
Diseases of the central nervous system, which once occupied a large component of the pharmaceutical industry research and development portfolio, have for many years played a smaller part in major pharma pipelines—primarily due to the well cited challenges in target validation, valid translational [...] Read more.
Diseases of the central nervous system, which once occupied a large component of the pharmaceutical industry research and development portfolio, have for many years played a smaller part in major pharma pipelines—primarily due to the well cited challenges in target validation, valid translational models, and clinical trial design. Unfortunately, this decline in research and development interest has occurred in tandem with an increase in the medical need—in part driven by the success in treating other chronic diseases, which then results in a greater overall longevity along with a higher prevalence of diseases associated with ageing. The lead modality for drug agents targeting the brain remains the traditionally small molecule, despite potential in gene-based therapies and antibodies, particularly in the hugely anticipated anti-amyloid field, clearly driven by the additional challenge of effective distribution to the relevant brain compartments. However, in recognition of the growing disease burden, advanced therapies are being developed in tandem with improved delivery options. Hence, methodologies which were initially restricted to systemic indications are now being actively explored for a range of CNS diseases—an important class of which include the protein degradation technologies. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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22 pages, 690 KiB  
Review
Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review
by Justin Matheson, Zoe Bourgault and Bernard Le Foll
Biomolecules 2022, 12(10), 1462; https://doi.org/10.3390/biom12101462 - 12 Oct 2022
Cited by 16 | Viewed by 4053
Abstract
Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as [...] Read more.
Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMed/Medline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria: eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD; two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC); two found antidepressant-like effects of CBD in males only; and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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40 pages, 2341 KiB  
Review
Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery
by Yeon Sun Lee
Biomolecules 2022, 12(9), 1241; https://doi.org/10.3390/biom12091241 - 5 Sep 2022
Cited by 8 | Viewed by 3685
Abstract
Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs [...] Read more.
Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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20 pages, 2793 KiB  
Review
Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity
by Harrison Rudd and Michal Toborek
Biomolecules 2022, 12(7), 894; https://doi.org/10.3390/biom12070894 - 26 Jun 2022
Cited by 5 | Viewed by 3589
Abstract
HIV can traverse the BBB using a Trojan horse-like mechanism. Hidden within infected immune cells, HIV can infiltrate the highly safeguarded CNS and propagate disease. Once integrated within the host genome, HIV becomes a stable provirus, which can remain dormant, evade detection by [...] Read more.
HIV can traverse the BBB using a Trojan horse-like mechanism. Hidden within infected immune cells, HIV can infiltrate the highly safeguarded CNS and propagate disease. Once integrated within the host genome, HIV becomes a stable provirus, which can remain dormant, evade detection by the immune system or antiretroviral therapy (ART), and result in rebound viraemia. As ART targets actively replicating HIV, has low BBB penetrance, and exposes patients to long-term toxicity, further investigation into novel therapeutic approaches is required. Viral proteins can be produced by latent HIV, which may play a synergistic role alongside ART in promoting neuroinflammatory pathophysiology. It is believed that the ability to specifically target these proviral reservoirs would be a vital driving force towards a cure for HIV infection. A novel drug design platform, using the in-tandem administration of several therapeutic approaches, can be used to precisely target the various components of HIV infection, ultimately leading to the eradication of active and latent HIV and a functional cure for HIV. The aim of this review is to explore the pitfalls of ART and potential novel therapeutic alternatives. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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