Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels.
Neuronal Kv7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal Kv7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing Kv7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal Kv7 channels, whereas its R-enantiomer was a negative modulator. By contrast, at the Kv7.1 and the large conductance Ca2+-activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA(A) receptors (alpha1beta2gamma2s and alpha2beta2gamma2s) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S- and R-forms exhibited opposing effects on neuronal Kv7 channel subtypes allowed us to assess the potential role of Kv7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive Kv7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the Kv7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal Kv7 channels are a target for developing novel anxiolytics.
Korsgaard
M P G
MP
NeuroSearch A/S, 93 Pederstrupvej, Ballerup, DK-2750, Denmark. mgk@neurosearch.dk
Hartz
B P
BP
Brown
W D
WD
Ahring
P K
PK
Strøbaek
D
D
Mirza
N R
NR
D000465:Algorithms; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D001007:Anxiety / Q000503:physiopathology / Q000523:psychology; D001259:Ataxia / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D018737:Hand Strength; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000819:agonists*; D018075:RNA, Complementary / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics; D013237:Stereoisomerism; D014982:Xenopus laevis
D014151:Anti-Anxiety Agents; C424388:BMS204352; D002219:Carbamates; D007211:Indoles; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; C496911:Kcnq1 protein, rat; D010655:Phenylenediamines; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; D011963:Receptors, GABA-A; C101866:ezogabine