Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs.
The Kv7 potassium channel family encompasses five members (from Kv7.1 to Kv7.5) having distinct expression pattern and functional role. Although Kv7.1 is prevalently expressed in the cardiac muscle, Kv7.2, Kv7.3, Kv7.4, and Kv7.5 are expressed in neural tissue. Mutations in Kv7.2 and/or Kv7.3 genes are responsible for an autosomal-dominant epilepsy of the newborn defined as benign familial neonatal seizures (BFNS), whereas defects in the Kv7.4 gene have been found in families affected by a rare form of nonsyndromic autosomal-dominant hearing loss (DFNA2). Compounds acting as direct activators of neuronal channels formed by Kv7 subunits have been approved for clinical use as analgesics or are in advanced stages of clinical evaluation as anticonvulsants; in addition to these indications, solid preclinical studies reveal their potential usefulness in other diseases characterized by neuronal hyperexcitability. In the present work, we will summarize the available evidence providing proof-of-principles that neuronal Kv7 channels are highly attractive pharmacological targets, review the molecular basis of their peculiar pharmacological sensitivity, introduce some newly synthesized I(KM) openers showing improved pharmacokinetic or pharmacodynamic properties compared to older congeners, and discuss the potential novel therapeutic application of neuronal Kv7 channels in diseases additional to epilepsy.
Section of Pharmacology, Department of Neuroscience, University of Naples Federico II, Naples, Italy.
Francesco
F
Miceli
Maria Virginia
MV
Soldovieri
Maria
M
Martire
Maurizio
M
Taglialatela
D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D020936:Epilepsy, Benign Neonatal / Q000188:drug therapy; D034381:Hearing Loss / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D051656:KCNQ Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051657:KCNQ1 Potassium Channel / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051658:KCNQ2 Potassium Channel / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051659:KCNQ3 Potassium Channel / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D010655:Phenylenediamines / Q000494:pharmacology / Q000627:therapeutic use
D000631:Aminopyridines; D002219:Carbamates; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C117367:KCNQ4 protein, human; C412231:KCNQ5 protein, human; D010655:Phenylenediamines; C101866:ezogabine; C034161:flupirtine