Details der Publikation - KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain

KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain

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: $ K_{i} $ sigma = 7.2*$ 10^{–8} $; $ K_{i} $ 5-$ HT_{1A} $ = 8.0*$ 10^{–7} $; $ ED_{50} $ 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; $ ED_{50} $ 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. Graphical abstract.

Medienart:	E-Artikel

Erscheinungsjahr:	2022
Erschienen:	2022

Enthalten in:	Zur Gesamtaufnahme - volume:75
Enthalten in:	Pharmacological reports - 75(2022), 1 vom: 19. Nov., Seite 128-165

Sprache:	Englisch

Beteiligte Personen:	Waszkielewicz, Anna [VerfasserIn] Marona, Henryk [VerfasserIn] Pańczyk-Straszak, Katarzyna [VerfasserIn] Filipek, Barbara [VerfasserIn] Rapacz, Anna [VerfasserIn] Sałat, Kinga [VerfasserIn] Kubacka, Monika [VerfasserIn] Cios, Agnieszka [VerfasserIn] Fedak, Filip [VerfasserIn] Walczak, Maria [VerfasserIn] Hubicka, Urszula [VerfasserIn] Kwiecień, Anna [VerfasserIn] Żuromska-Witek, Barbara [VerfasserIn] Szafrański, Przemysław W. [VerfasserIn] Koczurkiewicz-Adamczyk, Paulina [VerfasserIn] Pękala, Elżbieta [VerfasserIn] Przejczowska-Pomierny, Katarzyna [VerfasserIn] Pociecha, Krzysztof [VerfasserIn] Wyska, Elżbieta [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	5-HT Aminoalkanols Analgesic Anticonvulsant Degradation studies Metabolites Neuropathic pain Pharmacokinetics Safety profile Sigma (σ) Synthesis

Anmerkungen:	© The Author(s) 2022

doi:	10.1007/s43440-022-00431-7

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	OLC213369336X

Internformat


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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. 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: $ K_{i} $ sigma = 7.2$ 10^{–8} $; $ K_{i} $ 5-$ HT_{1A} $ = 8.0$ 10^{–7} $; $ ED_{50} $ 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; $ ED_{50} $ 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. Graphical abstract
650		4	\|a Aminoalkanols
650		4	\|a Synthesis
650		4	\|a Degradation studies
650		4	\|a Anticonvulsant
650		4	\|a Analgesic
650		4	\|a Neuropathic pain
650		4	\|a Sigma (σ)
650		4	\|a 5-HT
650		4	\|a Safety profile
650		4	\|a Pharmacokinetics
650		4	\|a Metabolites
700	1		\|a Marona, Henryk \|4 aut
700	1		\|a Pańczyk-Straszak, Katarzyna \|4 aut
700	1		\|a Filipek, Barbara \|4 aut
700	1		\|a Rapacz, Anna \|4 aut
700	1		\|a Sałat, Kinga \|4 aut
700	1		\|a Kubacka, Monika \|4 aut
700	1		\|a Cios, Agnieszka \|4 aut
700	1		\|a Fedak, Filip \|4 aut
700	1		\|a Walczak, Maria \|4 aut
700	1		\|a Hubicka, Urszula \|4 aut
700	1		\|a Kwiecień, Anna \|4 aut
700	1		\|a Żuromska-Witek, Barbara \|4 aut
700	1		\|a Szafrański, Przemysław W. \|4 aut
700	1		\|a Koczurkiewicz-Adamczyk, Paulina \|4 aut
700	1		\|a Pękala, Elżbieta \|4 aut
700	1		\|a Przejczowska-Pomierny, Katarzyna \|4 aut
700	1		\|a Pociecha, Krzysztof \|4 aut
700	1		\|a Wyska, Elżbieta \|4 aut
773	0	8	\|i Enthalten in \|t Pharmacological reports \|d Springer International Publishing, 1998 \|g 75(2022), 1 vom: 19. Nov., Seite 128-165 \|h Online-Ressource \|w (DE-627)375964215 \|w (DE-600)2129019-2 \|w (DE-576)281237727 \|x 2299-5684 \|7 nnns
773	1	8	\|g volume:75 \|g year:2022 \|g number:1 \|g day:19 \|g month:11 \|g pages:128-165
856	4	0	\|u https://dx.doi.org/10.1007/s43440-022-00431-7 \|z kostenfrei \|3 Volltext
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912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2015
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912			\|a GBV_ILN_2522
912			\|a GBV_ILN_2548
912			\|a GBV_ILN_4035
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4046
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4242
912			\|a GBV_ILN_4246
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4251
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
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912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4326
912			\|a GBV_ILN_4328
912			\|a GBV_ILN_4333
912			\|a GBV_ILN_4334
912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4336
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951			\|a AR
952			\|d 75 \|j 2022 \|e 1 \|b 19 \|c 11 \|h 128-165

KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain

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