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
Ádám István Horváth,
Nikolett Szentes,
Valéria Tékus,
Maja Payrits,
Éva Szőke,
Emőke Oláh,
András Garami,
Eszter Fliszár-Nyúl,
Miklós Poór,
Cecília Sár,
Tamás Kálai,
Szilárd Pál,
Krisztina Percze,
Éva Nagyné Scholz,
Tamás Mészáros,
Blanka Tóth,
Péter Mátyus,
Zsuzsanna Helyes
Affiliations
Ádám István Horváth
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary
Nikolett Szentes
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary
Valéria Tékus
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary
Maja Payrits
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary
Éva Szőke
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary
Emőke Oláh
Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
András Garami
Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
Eszter Fliszár-Nyúl
Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary
Miklós Poór
Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary
Cecília Sár
Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary
Tamás Kálai
Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary
Szilárd Pál
Institute of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary
Krisztina Percze
Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary
Éva Nagyné Scholz
Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary
Tamás Mészáros
Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary
Blanka Tóth
Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
Péter Mátyus
Institute of Digital Health Sciences, Faculty of Health and Public Services, Semmelweis University, H-1094 Budapest, Hungary
Zsuzsanna Helyes
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary
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.