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Design and Development of New Compounds/Strategies for the Neuropathic Pain...
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Design and Development of New Compounds/Strategies for the Neuropathic Pain Management

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 13008

Special Issue Editors

Dr. Krzysztof Kamiński

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
Interests: drug design and development; multitargeted compounds; neurological disorders (epilepsy, neuropathic pain); in vitro binding/functional studies; new mechanism of action; in vivo preclinical studies
Dr. Rafal M. Kaminski

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
Interests: drug discovery and development; translational medicine; neurological and neuropsychiatric disorders; genetics; systems biology

Special Issue Information

Dear Colleagues,

In this Special Issue we would like to focus the attention of the readers on the design and development of new drug candidates as well as novel therapeutic strategies for the treatment of neuropathic pain. It should be stressed herein, that the aforementioned condition belongs to the most frequent and debilitating neurological disorders, affecting approximately 7–10% of the global population. Due to its complex pathogenesis, neuropathic pain is characterized by a high degree of resistance to currently available therapies. Uncontrolled pain sensation negatively impacts patients’ quality of life and may cause numerous psychiatric disturbances, such as depression, anxiety or cognitive difficulties. Consequently, the search for new, more effective drugs or novel therapeutic strategies is urgently needed to address the remaining unmet need in this condition. Therefore, the main aim of the current Special Issue focuses on multidisciplinary studies, involving design and synthesis, as well as in vitro and in vivo characterization of new analgesic drug candidates. Prospective contributions are encouraged in the form of original research; however, concise review articles are also acceptable. The papers describing novel scientific hypotheses pertaining to neuropathic pain or new molecular targets for analgesics (including both selective and multi-targeted ligands), are particularly welcomed in this Special Issue of Molecules.

Dr. Krzysztof Kamiński
Dr. Rafal M. Kaminski
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. 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

  • neuropathic pain
  • drug design and development
  • drug targets
  • in vitro studies

Published Papers (5 papers)

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Research

11 pages, 1293 KiB  
Article
The Involvement of l-Arginine-Nitric Oxide-cGMP-ATP-Sensitive K+ Channel Pathway in Antinociception of BBHC, a Novel Diarylpentanoid Analogue, in Mice Model
by Hui Ming Ong, Ahmad Farhan Ahmad Azmi, Sze Wei Leong, Faridah Abas, Enoch Kumar Perimal, Ahmad Akira Omar Farouk, Daud Ahmad Israf and Mohd Roslan Sulaiman
Molecules 2021, 26(24), 7431; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26247431 - 08 Dec 2021
Cited by 2 | Viewed by 1999
Abstract
The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was [...] Read more.
The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperitoneal pre-treatment of l-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K+ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC’s antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p < 0.05). Altogether, these findings suggest that the systemic administration of BBHC is able to establish a significant antinociceptive effect in a mice model of chemically induced pain. BBHC’s antinociception is shown to be mediated by the involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway, without any potential sedative or muscle relaxant concerns. Full article
(This article belongs to the Special Issue Design and Development of New Compounds/Strategies for the Neuropathic Pain Management)
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27 pages, 4694 KiB  
Article
The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice
by Kinga Sałat, Anna Furgała-Wojas and Robert Sałat
Molecules 2021, 26(12), 3577; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26123577 - 11 Jun 2021
Cited by 12 | Viewed by 3173
Abstract
The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in [...] Read more.
The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain. Full article
(This article belongs to the Special Issue Design and Development of New Compounds/Strategies for the Neuropathic Pain Management)
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16 pages, 1577 KiB  
Article
Synthesis, Anticonvulsant, and Antinociceptive Activity of New 3-(2-Chlorophenyl)- and 3-(3-Chlorophenyl)-2,5-dioxo-pyrrolidin-1-yl-acetamides
by Małgorzata Góra, Anna Czopek, Anna Rapacz, Anna Gębska, Katarzyna Wójcik-Pszczoła, Elżbieta Pękala and Krzysztof Kamiński
Molecules 2021, 26(6), 1564; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26061564 - 12 Mar 2021
Cited by 10 | Viewed by 2400
Abstract
The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure [...] Read more.
The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione (6) showed more beneficial ED50 and protective index values than the reference drug—valproic acid (68.30 mg/kg vs. 252.74 mg/kg in the MES test and 28.20 mg/kg vs. 130.64 mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds—namely, 6 and 19—was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABAA and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound 6 relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds 6 and 19 were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect. Full article
(This article belongs to the Special Issue Design and Development of New Compounds/Strategies for the Neuropathic Pain Management)
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14 pages, 1088 KiB  
Article
Wide-Range Measurement of Thermal Preference—A Novel Method for Detecting Analgesics Reducing Thermally-Evoked Pain in Mice
by Kinga Sałat, Anna Furgała-Wojas, Michał Awtoniuk and Robert Sałat
Molecules 2021, 26(3), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26030612 - 25 Jan 2021
Cited by 2 | Viewed by 2453
Abstract
Background: Wide use of oxaliplatin as an antitumor drug is limited by severe neuropathy with pharmacoresistant cold hypersensitivity as the main symptom. Novel analgesics to attenuate cold hyperalgesia and new methods to detect drug candidates are needed. Methods: We developed a method to [...] Read more.
Background: Wide use of oxaliplatin as an antitumor drug is limited by severe neuropathy with pharmacoresistant cold hypersensitivity as the main symptom. Novel analgesics to attenuate cold hyperalgesia and new methods to detect drug candidates are needed. Methods: We developed a method to study thermal preference of oxaliplatin-treated mice and assessed analgesic activity of intraperitoneal duloxetine and pregabalin used at 30 mg/kg. A prototype analgesiameter and a broad range of temperatures (0–45 °C) were used. Advanced methods of image analysis (deep learning and machine learning) enabled us to determine the effectiveness of analgesics. The loss or reversal of thermal preference of oxaliplatin-treated mice was a measure of analgesia. Results: Duloxetine selectively attenuated cold-induced pain at temperatures between 0 and 10 °C. Pregabalin-treated mice showed preference towards a colder plate of the two used at temperatures between 0 and 45 °C. Conclusion: Unlike duloxetine, pregabalin was not selective for temperatures below thermal preferendum. It influenced pain sensation at a much wider range of temperatures applied. Therefore, for the attenuation of cold hypersensitivity duloxetine seems to be a better than pregabalin therapeutic option. We propose wide-range measurements of thermal preference as a novel method for the assessment of analgesic activity in mice. Full article
(This article belongs to the Special Issue Design and Development of New Compounds/Strategies for the Neuropathic Pain Management)
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12 pages, 1713 KiB  
Article
Zingiber officinale Roscoe Rhizomes Attenuate Oxaliplatin-Induced Neuropathic Pain in Mice
by Ji Hwan Lee, Daeun Min, Donghun Lee and Woojin Kim
Molecules 2021, 26(3), 548; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26030548 - 21 Jan 2021
Cited by 14 | Viewed by 2310
Abstract
Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used [...] Read more.
Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of Z. officinale (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT1A (NAN-190, i.t., 1 μg), but not with the antagonist 5-HT2A (ketanserin, i.t., 1 μg), significantly blocked the analgesic effect of Z. officinale against both cold and mechanical allodynia. However, 5-HT3 antagonist (MDL-72222, i.t., 15 μg) administration only blocked the anti-allodynic effect of Z. officinale against cold allodynia. Real-time PCR analysis demonstrated that Z. officinale significantly increased the mRNA expression of the spinal 5-HT1A receptor that was downregulated after oxaliplatin injection. These results suggest that Z. officinale may be a viable treatment option for oxaliplatin-induced neuropathic pain. Full article
(This article belongs to the Special Issue Design and Development of New Compounds/Strategies for the Neuropathic Pain Management)
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