KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain
© 2022. The Author(s)..
BACKGROUND: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity.
METHODS: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation.
RESULTS: Selected results for KM-408: Ki sigma = 7.2*10-8; Ki 5-HT1A = 8.0*10-7; ED50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)-active at 30 mg/kg; SNL (rats, ip)-active at 6 mg/kg; STZ-induced pain (mice, ip)-active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)-active at 30 mg/kg; ED50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)-active at 0.5%; corneal anesthesia (guinea pigs)-active at 0.125%; infiltration anesthesia (guinea pigs)-active at 0.125%.
CONCLUSIONS: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:75 |
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| Enthalten in: |
Pharmacological reports : PR - 75(2023), 1 vom: 16. Feb., Seite 128-165 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Waszkielewicz, Anna [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.02.2023 Date Revised 03.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s43440-022-00431-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349149828 |
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| 100 | 1 | |a Waszkielewicz, Anna |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain |
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| 500 | |a Date Revised 03.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a BACKGROUND: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity | ||
| 520 | |a METHODS: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation | ||
| 520 | |a RESULTS: Selected results for KM-408: Ki sigma = 7.2*10-8; Ki 5-HT1A = 8.0*10-7; ED50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)-active at 30 mg/kg; SNL (rats, ip)-active at 6 mg/kg; STZ-induced pain (mice, ip)-active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)-active at 30 mg/kg; ED50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)-active at 0.5%; corneal anesthesia (guinea pigs)-active at 0.125%; infiltration anesthesia (guinea pigs)-active at 0.125% | ||
| 520 | |a CONCLUSIONS: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Degradation studies | |
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| 650 | 4 | |a Neuropathic pain | |
| 650 | 4 | |a Pharmacokinetics | |
| 650 | 4 | |a Safety profile | |
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| 700 | 1 | |a Rapacz, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Sałat, Kinga |e verfasserin |4 aut | |
| 700 | 1 | |a Kubacka, Monika |e verfasserin |4 aut | |
| 700 | 1 | |a Cios, Agnieszka |e verfasserin |4 aut | |
| 700 | 1 | |a Fedak, Filip |e verfasserin |4 aut | |
| 700 | 1 | |a Walczak, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Hubicka, Urszula |e verfasserin |4 aut | |
| 700 | 1 | |a Kwiecień, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Żuromska-Witek, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Szafrański, Przemysław W |e verfasserin |4 aut | |
| 700 | 1 | |a Koczurkiewicz-Adamczyk, Paulina |e verfasserin |4 aut | |
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| 700 | 1 | |a Wyska, Elżbieta |e verfasserin |4 aut | |
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