1. KM-416, a novel phenoxyalkylaminoalkanol derivative with anticonvulsant properties exerts analgesic, local anesthetic, and antidepressant-like activities. Pharmacodynamic, pharmacokinetic, and forced degradation studies.
- Author
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Kubacka M, Rapacz A, Sałat K, Filipek B, Cios A, Pociecha K, Wyska E, Hubicka U, Żuromska-Witek B, Kwiecień A, Marona H, and Waszkielewicz AM
- Subjects
- Analgesics chemistry, Analgesics pharmacokinetics, Anesthetics, Local chemistry, Anesthetics, Local pharmacokinetics, Animals, Anticonvulsants chemistry, Anticonvulsants pharmacokinetics, Antidepressive Agents chemistry, Antidepressive Agents pharmacokinetics, Area Under Curve, Brain metabolism, Capsaicin pharmacology, Diabetic Neuropathies drug therapy, Drug Stability, Epilepsy, Guinea Pigs, Hemodynamics drug effects, Male, Mice, Neuralgia drug therapy, Pain Measurement, Patch-Clamp Techniques, Rats, Rats, Wistar, Sodium Channel Blockers pharmacology, Analgesics pharmacology, Anesthetics, Local pharmacology, Anticonvulsants pharmacology, Antidepressive Agents pharmacology
- Abstract
Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT
1A , α2 -receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na+ currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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