Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of potassium channels generally reduces cellular excitability, making potassium channel openers potential drug candidates for the treatment of diseases related to hyperexcitabilty such as epilepsy, neuropathic pain, and neurodegeneration. Two compounds, BMS-204352 and retigabine, presently in clinical trials for the treatment of stroke and epilepsy, respectively, have been proposed to exert their protective action via an activation of potassium channels. Here we show that KCNQ4 channels, stably expressed in HEK293 cells, were activated by retigabine and BMS-204352 in a reversible and concentration-dependent manner in the concentration range 0.1-10 microM. Both compounds shifted the KCNQ4 channel activation curves towards more negative potentials by about 10 mV. Further, the maximal current obtainable at large positive voltages was also increased concentration-dependently by both compounds. Finally, a pronounced slowing of the deactivation kinetics was induced in particular by BMS-204352. The M-current blocker linopirdine inhibited the baseline current, as well as the BMS-204352-induced activation of the KCNQ4 channels. KCNQ2, KCNQ2/Q3, and KCNQ3/Q4 channels were activated to a similar degree as KCNQ4 channels by 10 microM of BMS-204352 and retigabine, respectively. The compounds are, thus, likely to be general activators of M-like currents.
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PMID:KCNQ4 channel activation by BMS-204352 and retigabine. 1137 59

Idiopathic epilepsies, which account for up to 40% of all epilepsies, are mainly caused by genetic factors. Most idiopathic epilepsies are due to oligogenic or multifactorial rather than monogenetic inheritance. Nevertheless, most of what is known today about the molecular genetics of idiopathic epilepsies has been found by analysing large families with rare monogenetic forms of the disease. For the first time, gene defects can be linked to certain epilepsies. Mutations in the CHRNA4 or CHRNB subunits of the neuronal nicotinic acetylcholine receptor lead to familial nocturnal frontal lobe epilepsy, while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been found to cause benign familial neonatal convulsions. The voltage-gated sodium channel subunits SCN1B, SCN1A and SCN2A as well as the GABRG2 subunit of the GABA(A) receptor are involved in the pathology of the newly described syndrome generalized epilepsy with febrile seizures plus. These rare monogenetic epilepsies can serve as models for further genetic analysis of the common forms of idiopathic epilepsies.
Eur J Pain 2002
PMID:Channelopathies can cause epilepsy in man. 1188 38

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [IK(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of IK(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. IK(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 microm) and XE991 (IC50, 0.26 microm) and enhanced by retigabine (10 microm). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that IK(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.
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PMID:KCNQ/M currents in sensory neurons: significance for pain therapy. 1290 83

Neuronal KCNQ (Kv7) channels (KCNQ2-5 or Kv7.2-7.5, disclosed to date) were discovered by virtue of their homology with a known cardiac channel involved in long QT syndrome (KvLQT or KCNQ1, Kv7.1) and first disclosed in 1998. The involvement of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) in a benign idiopathic neonatal epilepsy, KCNQ4 (Kv7.4) in a form of congenital deafness, and the discovery that neuronal KCNQ heteromultimers were among the molecular substrates of M-channels, resulted in a high level of interest for potential drug development strategies. A number of small-molecule modulators were quickly identified, including openers or activators such as the antiepileptic drug candidate retigabine and the structurally-related analgesic drug flupirtine (Katadolon trade mark Asta Medica), and a group of KCNQ channel inhibitors/blockers originally developed for cognition enhancement. All of these data have suggested a rich target profile for modulators of neuronal KCNQ channels, including a variety of neuronal hyperexcitability disorders and conditions for openers, such as the epilepsies, acute pain, neuropathic pain, migraine pain and some neurodegenerative and psychiatric disorders. KCNQ blockers could likewise have utility in disorders characterised by neuronal hypoactivity, including cognition enhancement and perhaps disorders of mood. Emerging patent literature suggests significant interest in neuronal KCNQ modulation in the pharmaceutical industry and significant chemical diversity concerning KCNQ modulation.
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PMID:The therapeutic potential of neuronal KCNQ channel modulators. 1464 Sep 9

The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel alpha subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC(50) = 25 microM) and diclofenac (EC(50) = 2.6 microM) resulted in the activation of KCNQ2/Q3 K(+) currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (-23 and -15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel alpha subunits. In contrast, they did not enhance KCNQ1 K(+) currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED(50) = 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.
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PMID:Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties. 1559 72

During the past five years, several members of the KCNQ potassium channel gene family have been identified with a high degree of CNS specificity. Within the KCNQ family, the combination of the KCNQ2/KCNQ3 proteins, and the KCNQ5/KCNQ3 arrangement has been identified as the molecular correlates of the different M-currents. Several lines of evidence are emerging demonstrating the importance of these channels in regulating neuronal excitability; for example, determination of the excitability threshold, firing properties, and responsiveness of neurons to synaptic inputs. Recent studies have shown that KCNQ openers have potential for the treatment of several CNS disorders characterized by neuronal hyperexcitability, such as migraine, epilepsy and neuropathic pain. This article reviews the recent developments of KCNQ potassium channel openers.
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PMID:Recent developments on KCNQ potassium channel openers. 1572 Feb 53

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.
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PMID:Retigabine: chemical synthesis to clinical application. 1586 50

Compounds that stimulate or inhibit M-channels (ie, voltage-gated potassium channels formed by KCNQ2, KCNQ3 and KCNQ5) have been evaluated in clinical trials for epilepsy, stroke and Alzheimer's disease. The importance of M-channel function in reducing neuronal excitability is underscored by the finding that KCNQ2/3 mutations causing mild reduction of M-channel activity are linked to neonatal epilepsy. M-channel openers decrease the hyperexcitability responsible for epileptic seizures, neuropathic pain and migraine. Conversely, M-channel blockers may enhance cognitive functions. The M-channel has thus emerged as a promising target for treating epilepsy, stroke, migraine, pain, dementia, anxiety and bipolar disorder.
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PMID:A potassium channel, the M-channel, as a therapeutic target. 1604 66

Inherited or de novo mutations in at least a dozen genes encoding ion channels may present as paroxysmal disorders during the neonatal period or first year of life. These channelopathies include genes encoding voltage-gated channels specific for sodium (SCN1A, SCN2A, SCN1B, SCN9A) and potassium (KCNQ2, KCNQ3) which account for a variety of epilepsy phenotypes ranging from mild, such as Benign familial neonatal seizures (BFNS) to severe, such as Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI) and the rare and unusual syndrome paroxysmal extreme pain disorder (PEPD). Ligand-gated channels involved include the GABA(A) receptor in a variety of epilepsy phenotypes and the human glycine receptor. Mutations in five genes encoding subunits of this receptor and accessory molecules underlie hyperekplexia or stiff-baby syndrome. All these conditions are rare but correct diagnosis is of value not only for genetic counselling but to allow the specific treatment which is available.
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PMID:Molecular genetics of infantile nervous system channelopathies. 1704 61

K(v)7.2-7.5 voltage-gated potassium channels (KCNQ2-5) are associated with M-current and known to distribute in the nociceptive sensory pathway (e.g., dorsal root ganglia and spinal cord). Opening of these channels leads to cell membrane hyperpolarization that results in decreased neuronal action potentials. Since, KCNQ/M-current is located in the visceral sensory system, we examined the anti-nociceptive effect of the KCNQ opener, retigabine, on visceral pain induced by an intracolonic injection of capsaicin in mice. Intraperitoneal administration of retigabine (1, 3 and 10 mg/kg) dose-dependently suppressed visceral pain behavior (i.e., the number of licking) induced by the capsaicin treatment and prolonged the latency to first licking. These data provide the first evidence that increased KCNQ channel conductance plays an inhibitory role in the visceral pain pathway.
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PMID:Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice. 1718 17


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