In vitro and in vivo characterization of Lu AA41178: A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders
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In vitro and in vivo characterization of Lu AA41178 : A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders. / Grupe, Morten; Bentzen, Bo Hjorth; Benned-Jensen, Tau; Nielsen, Vibeke; Frederiksen, Kristen; Jensen, Henrik Sindal; Jacobsen, Anne-Marie; Skibsbye, Lasse; Sams, Anette Graven; Grunnet, Morten; Rottlander, Mario; Bastlund, Jesper Frank.
In: European Journal of Pharmacology, Vol. 887, 173440, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - In vitro and in vivo characterization of Lu AA41178
T2 - A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders
AU - Grupe, Morten
AU - Bentzen, Bo Hjorth
AU - Benned-Jensen, Tau
AU - Nielsen, Vibeke
AU - Frederiksen, Kristen
AU - Jensen, Henrik Sindal
AU - Jacobsen, Anne-Marie
AU - Skibsbye, Lasse
AU - Sams, Anette Graven
AU - Grunnet, Morten
AU - Rottlander, Mario
AU - Bastlund, Jesper Frank
PY - 2020
Y1 - 2020
N2 - Activation of the voltage-gated Kv7 channels holds therapeutic promise in several neurological and psychiatric disorders, including epilepsy, schizophrenia, and depression. Here, we present a pharmacological characterization of Lu AA41178, a novel, pan-selective Kv7.2-7.5 opener, using both in vitro assays and a broad range of in vivo assays with relevance to epilepsy, schizophrenia, and depression.Electrophysiological characterization in Xenopus oocytes expressing human Kv7.2-Kv7.5 confirmed Lu AA41178 as a pan-selective opener of Kv7 channels by significantly left-shifting the activation threshold. Additionally, Lu AA41178 was tested in vitro for off-target effects, demonstrating a clean Kv7-selective profile, with no impact on common cardiac ion channels, and no potentiating activity on GABAA channels.Lu AA41178 was evaluated across preclinical in vivo assays with relevance to neurological and psychiatric disorders. In the maximum electroshock seizure threshold test and PTZ seizure threshold test, Lu AA41178 significantly increased the seizure thresholds in mice, demonstrating anticonvulsant efficacy. Lu AA41178 demonstrated antipsychotic-like activity by reducing amphetamine-induced hyperlocomotion in mice as well as lowering conditioned avoidance responses in rats. In the mouse forced swim test, a model with antidepressant predictivity, Lu AA41178 significantly reduced immobility. Additionally, behavioral effects typically observed with Kv7 openers was also characterized. In vivo assays were accompanied by plasma and brain exposures, revealing minimum effective plasma levelsLu AA41178, a potent opener of neuronal Kv7 channels demonstrate efficacy in assays of epilepsy, schizophrenia and depression and might serve as a valuable tool for exploring the role of Kv7 channels in both neurological and psychiatric disorders.
AB - Activation of the voltage-gated Kv7 channels holds therapeutic promise in several neurological and psychiatric disorders, including epilepsy, schizophrenia, and depression. Here, we present a pharmacological characterization of Lu AA41178, a novel, pan-selective Kv7.2-7.5 opener, using both in vitro assays and a broad range of in vivo assays with relevance to epilepsy, schizophrenia, and depression.Electrophysiological characterization in Xenopus oocytes expressing human Kv7.2-Kv7.5 confirmed Lu AA41178 as a pan-selective opener of Kv7 channels by significantly left-shifting the activation threshold. Additionally, Lu AA41178 was tested in vitro for off-target effects, demonstrating a clean Kv7-selective profile, with no impact on common cardiac ion channels, and no potentiating activity on GABAA channels.Lu AA41178 was evaluated across preclinical in vivo assays with relevance to neurological and psychiatric disorders. In the maximum electroshock seizure threshold test and PTZ seizure threshold test, Lu AA41178 significantly increased the seizure thresholds in mice, demonstrating anticonvulsant efficacy. Lu AA41178 demonstrated antipsychotic-like activity by reducing amphetamine-induced hyperlocomotion in mice as well as lowering conditioned avoidance responses in rats. In the mouse forced swim test, a model with antidepressant predictivity, Lu AA41178 significantly reduced immobility. Additionally, behavioral effects typically observed with Kv7 openers was also characterized. In vivo assays were accompanied by plasma and brain exposures, revealing minimum effective plasma levelsLu AA41178, a potent opener of neuronal Kv7 channels demonstrate efficacy in assays of epilepsy, schizophrenia and depression and might serve as a valuable tool for exploring the role of Kv7 channels in both neurological and psychiatric disorders.
KW - Kv7
KW - KCNQ
KW - Lu AA41178
KW - Retigabine
KW - Epilepsy
KW - Kv7 opener
KW - RETIGABINE EZOGABINE
KW - SOCIAL DEFEAT
KW - ANIMAL-MODELS
KW - ANTICONVULSANT
KW - NEURONS
KW - EXCITABILITY
KW - ICA-27243
KW - KCNQ2
KW - N-(6-CHLORO-PYRIDIN-3-YL)-3,4-DIFLUORO-BENZAMIDE
KW - SUSCEPTIBILITY
U2 - 10.1016/j.ejphar.2020.173440
DO - 10.1016/j.ejphar.2020.173440
M3 - Journal article
C2 - 32745603
VL - 887
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
M1 - 173440
ER -
ID: 251947524