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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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