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

Biomedicines

Blanka Tóth¹  Krisztina Percze²  Éva Nagyné Scholz²  Tamás Mészáros²  Maja Payrits³  Zsuzsanna Helyes³  Valéria Tékus³  Nikolett Szentes³  Éva Szőke³  Ádám István Horváth³  Eszter Fliszár-Nyúl⁴  Miklós Poór⁴  Emőke Oláh⁵  András Garami⁵  Péter Mátyus⁶  Cecília Sár⁷  Tamás Kálai⁷  Szilárd Pál⁸ 

[1] Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary;Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary;Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary;Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary;Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary;Institute of Digital Health Sciences, Faculty of Health and Public Services, Semmelweis University, H-1094 Budapest, Hungary;Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary;Institute of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary;

关键词: semicarbazide-sensitive amine oxidase;    vascular adhesion protein-1;    partial sciatic nerve ligation;    traumatic neuropathy;    SZV 1287;    transient receptor potential vanilloid 1;   

DOI  :  10.3390/biomedicines9070749

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown