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KA‐104, a new multitargeted anticonvulsant with potent antinociceptive activity in preclinical models
Author(s) -
Kamiński Krzysztof,
Mogilski Szczepan,
Abram Michał,
Rapacz Anna,
Latacz Gniewomir,
Szulczyk Bartłomiej,
Walczak Maria,
Kuś Kamil,
Matyjaszczyk Karolina,
Kamiński Rafał M.
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16669
Subject(s) - anticonvulsant , pharmacology , neuropathic pain , pharmacokinetics , chemistry , adme , nociception , analgesic , sodium channel , mexiletine , pharmacodynamics , anesthesia , medicine , sodium , epilepsy , receptor , biochemistry , psychiatry , organic chemistry
Objective The main objective of the present work was to assess the utility of KA‐104 as potential therapy for drug‐resistant seizures and neuropathic pain, and to characterize its druglike properties in a series of absorption, distribution, metabolism, excretion and toxicity (ADME‐Tox) studies. We also aimed to establish its mechanism of action in electrophysiological studies. Methods The activity of KA‐104 against drug‐resistant seizures was tested in the mouse 6‐Hz (44‐mA) model, whereas the antinociceptive activity was assessed with the capsaicin‐ and oxaliplatin‐induced pain models in mice. The patch‐clamp technique was used to study the influence of KA‐104 on fast voltage‐gated sodium currents in rat prefrontal cortex pyramidal neurons. The pharmacokinetic profile was determined after intraperitoneal (ip) injection in mice. The in vitro ADME‐Tox properties were studied by applying routine testing procedures. Results KA‐104 was effective in the 6‐Hz (44‐mA) model (median effective dose [ED 50 ] = 73.2 mg/kg) and revealed high efficacy in capsaicin‐induced neurogenic pain as well as in oxaliplatin‐induced neuropathic pain in mice. Patch‐clamp technique showed that KA‐104 reversibly inhibits voltage‐gated sodium currents. KA‐104 was rapidly absorbed after the ip injection and showed relatively good penetration through the blood‐brain barrier. This molecule was also characterized by high passive permeability, moderate influence on CYP2C9, and negligible hepatotoxicity on HepG2 cells. Significance The results reported herein indicate that KA‐104 is a new wide‐spectrum multitargeted anticonvulsant with favorable in vitro ADME‐Tox properties. Importantly, this compound may also prove to become an interesting and hopefully more effective therapeutic option for treatment of neuropathic pain.