Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

Andreev, Yaroslav A.; Osmakov, Dmitry I.; Koshelev, Sergey G.; Maleeva, Ekaterina E.; Logashina, Yulia A.; Паликов, В. А.; Palikova, Yu. A.; Dyachenko, Igor A.; Kozlov, Sergey A.

doi:10.3390/md16120500

Cited by 29 publications

(43 citation statements)

References 57 publications

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“…and intramuscular (i.m.) administration, as was reported for the natural compound [25]. As demonstrated above, sevanol keeps the best activity among analogues synthesized in this work, and therefore, it is the most promising molecule for further studies.…”

Section: Analgesic Effects Of Sevanolsupporting

confidence: 80%

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

et al. 2020

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Among acid-sensing ion channels (ASICs), ASIC1a and ASIC3 subunits are the most widespread and prevalent in physiological and pathophysiological conditions. They participate in synaptic plasticity, learning and memory, as well as the perception of inflammatory and neurological pain, making these channels attractive pharmacological targets. Sevanol, a natural lignan isolated from Thymus armeniacus, inhibits the activity of ASIC1a and ASIC3 isoforms, and has a significant analgesic and anti-inflammatory effect. In this work, we described the efficient chemical synthesis scheme of sevanol and its analogues, which allows us to analyze the structure–activity relationships of the different parts of this molecule. We found that the inhibitory activity of sevanol and its analogues on ASIC1a and ASIC3 channels depends on the number and availability of the carboxyl groups of the molecule. At the structural level, we predicted the presence of a sevanol binding site based on the presence of molecular docking in the central vestibule of the ASIC1a channel. We predicted that this site could also be occupied in part by the FRRF-amide peptide, and the competition assay of sevanol with this peptide confirmed this prediction. The intravenous (i.v.), intranasal (i.n.) and, especially, oral (p.o.) administration of synthetic sevanol in animal models produced significant analgesic and anti-inflammatory effects. Both non-invasive methods of sevanol administration (i.n. and p.o.) showed greater efficacy than the invasive (i.v.) method, thus opening new horizons for medicinal uses of sevanol.

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Section: Analgesic Effects Of Sevanolsupporting

confidence: 80%

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

et al. 2020

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“…Sevanol also inhibits the rat ASIC1a channel but with less efficacy ( Dubinnyi et al., 2012 ). In models of acetic acid-induced writhing and CFA-induced thermal hyperalgesia tests, sevanol showed dose-dependent (range from 0.001 to 10 mg/kg), pronounced analgesic and anti-inflammatory effects ( Andreev et al., 2018 ).…”

Section: Natural Ligands Of Acid-sensing Ion Channelsmentioning

confidence: 99%

“…It completely blocks the transient component with an IC 50 of 10 µM, and only by 48% inhibits the sustained component with an IC 50 of 1.44 µM ( Osmakov et al., 2013 ). Intramuscular or intravenous injection of Ugr 9-1 (0.01–1 mg/kg) produced a significant analgesic effect in the acid-induced pain model and the complete Freund’s adjuvant-induced thermal hyperalgesia test ( Osmakov et al., 2013 ; Andreev et al., 2018 ).…”

Section: Natural Ligands Of Acid-sensing Ion Channelsmentioning

confidence: 99%

“…Peptide APETx2 was reported to produce a significant analgesic effect in several models of pain such as acid-induced pain, CFA-induced hyperalgesia, migraine-related pain, and postoperative pain ( Karczewski et al., 2010 ; Deval et al., 2011 ; Callejo et al., 2015 ; Andreev et al., 2018 ; Lee et al., 2018 ; Holton et al., 2020 ). However, it should be taken into consideration that the ability of APETx2 to affect various subtypes of ASICs and several voltage-gated channels (as discussed above) limits connection between the effects of this peptide in vivo with ASIC3 function.…”

Section: Perspectives In Therapeutic Developmentmentioning

confidence: 99%

“…However, it should be taken into consideration that the ability of APETx2 to affect various subtypes of ASICs and several voltage-gated channels (as discussed above) limits connection between the effects of this peptide in vivo with ASIC3 function. Nevertheless, more selective to ASIC3, animal toxin Ugr 9-1 significantly reduces inflammatory and acid-induced pain at doses 0.01–1 mg/kg after intravenous or intramuscular administration ( Osmakov et al., 2013 ; Andreev et al., 2018 ). Sevanol, the compound isolated from thyme, revealed high analgesic activity and was even more effective than peptide inhibitors of ASIC3, as was shown in a comparative study ( Andreev et al., 2018 ).…”

Section: Perspectives In Therapeutic Developmentmentioning

confidence: 99%

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Animal, Herb, and Microbial Toxins for Structural and Pharmacological Study of Acid-Sensing Ion Channels

Osmakov¹,

Khasanov²,

Andreev³

et al. 2020

Front. Pharmacol.

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Acid-sensing ion channels (ASICs) are of the most sensitive molecular sensors of extracellular pH change in mammals. Six isoforms of these channels are widely represented in membranes of neuronal and non-neuronal cells, where these molecules are involved in different important regulatory functions, such as synaptic plasticity, learning, memory, and nociception, as well as in various pathological states. Structural and functional studies of both wild-type and mutant ASICs are essential for human care and medicine for the efficient treatment of socially significant diseases and ensure a comfortable standard of life. Ligands of ASICs serve as indispensable tools for these studies. Such bioactive compounds can be synthesized artificially. However, to date, the search for such molecules has been most effective amongst natural sources, such as animal venoms or plants and microbial extracts. In this review, we provide a detailed and comprehensive structural and functional description of natural compounds acting on ASICs, as well as the latest information on structural aspects of their interaction with the channels. Many of the examples provided in the review demonstrate the undoubted fundamental and practical successes of using natural toxins. Without toxins, it would not be possible to obtain data on the mechanisms of ASICs’ functioning, provide detailed study of their pharmacological properties, or assess the contribution of the channels to development of different pathologies. The selectivity to different isoforms and variety in the channel modulation mode allow for the appraisal of prospective candidates for the development of new drugs.

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Immunomodulatory activities and biomedical applications of melittin and its recent advances

Jafari,

Sadeghi,

Dehaghi

et al. 2024

Archiv der Pharmazie

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Melittin (MLT), a peptide containing 26 amino acids, is a key constituent of bee venom. It comprises ∼40%–60% of the venom's dry weight and is the main pricing index for bee venom, being the causative factor of pain. The unique properties of MLT extracted from bee venom have made it a very valuable active ingredient in the pharmaceutical industry as this cationic and amphipathic peptide has propitious effects on human health in diverse biological processes. It has the ability to strongly impact the membranes of cells and display hemolytic activity with anticancer characteristics. However, the clinical application of MLT has been limited by its severe hemolytic activity, which poses a challenge for therapeutic use. By employing more efficient mechanisms, such as modifying the MLT sequence, genetic engineering, and nano‐delivery systems, it is anticipated that the limitations posed by MLT can be overcome, thereby enabling its wider application in therapeutic contexts. This review has outlined recent advancements in MLT's nano‐delivery systems and genetically engineered cells expressing MLT and provided an overview of where the MLTMLT's platforms are and where they will go in the future with the challenges ahead. The focus is on exploring how these approaches can overcome the limitations associated with MLT's hemolytic activity and improve its selectivity and efficacy in targeting cancer cells. These advancements hold promise for the creation of innovative and enhanced therapeutic approaches based on MLT for the treatment of cancer.

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Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

Cited by 29 publications

References 57 publications

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

Animal, Herb, and Microbial Toxins for Structural and Pharmacological Study of Acid-Sensing Ion Channels

Immunomodulatory activities and biomedical applications of melittin and its recent advances

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