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Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain
SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301340/ https://www.ncbi.nlm.nih.gov/pubmed/34209525 http://dx.doi.org/10.3390/biomedicines9070749 |
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author | Horváth, Ádám István Szentes, Nikolett Tékus, Valéria Payrits, Maja Szőke, Éva Oláh, Emőke Garami, András Fliszár-Nyúl, Eszter Poór, Miklós Sár, Cecília Kálai, Tamás Pál, Szilárd Percze, Krisztina Scholz, Éva Nagyné Mészáros, Tamás Tóth, Blanka Mátyus, Péter Helyes, Zsuzsanna |
author_facet | Horváth, Ádám István Szentes, Nikolett Tékus, Valéria Payrits, Maja Szőke, Éva Oláh, Emőke Garami, András Fliszár-Nyúl, Eszter Poór, Miklós Sár, Cecília Kálai, Tamás Pál, Szilárd Percze, Krisztina Scholz, Éva Nagyné Mészáros, Tamás Tóth, Blanka Mátyus, Péter Helyes, Zsuzsanna |
author_sort | Horváth, Ádám István |
collection | PubMed |
description | SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate. |
format | Online Article Text |
id | pubmed-8301340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83013402021-07-24 Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain Horváth, Ádám István Szentes, Nikolett Tékus, Valéria Payrits, Maja Szőke, Éva Oláh, Emőke Garami, András Fliszár-Nyúl, Eszter Poór, Miklós Sár, Cecília Kálai, Tamás Pál, Szilárd Percze, Krisztina Scholz, Éva Nagyné Mészáros, Tamás Tóth, Blanka Mátyus, Péter Helyes, Zsuzsanna Biomedicines Article SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate. MDPI 2021-06-29 /pmc/articles/PMC8301340/ /pubmed/34209525 http://dx.doi.org/10.3390/biomedicines9070749 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Horváth, Ádám István Szentes, Nikolett Tékus, Valéria Payrits, Maja Szőke, Éva Oláh, Emőke Garami, András Fliszár-Nyúl, Eszter Poór, Miklós Sár, Cecília Kálai, Tamás Pál, Szilárd Percze, Krisztina Scholz, Éva Nagyné Mészáros, Tamás Tóth, Blanka Mátyus, Péter Helyes, Zsuzsanna Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain |
title | Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain |
title_full | Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain |
title_fullStr | Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain |
title_full_unstemmed | Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain |
title_short | Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain |
title_sort | proof-of-concept for the analgesic effect and thermoregulatory safety of orally administered multi-target compound szv 1287 in mice: a novel drug candidate for neuropathic pain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301340/ https://www.ncbi.nlm.nih.gov/pubmed/34209525 http://dx.doi.org/10.3390/biomedicines9070749 |
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