Disease relevance of C13826

• Compared with young men, young women had higher retigabine maximum concentration (56%) and exposure (20%) but similar clearance (0.68 L x h(-1) x kg(-1)); these differences were related to differences in body weight [1].
• The antidystonic effect of retigabine (10 mg kg(-1) i.p.) was counteracted by XE-991 (3 mg kg(-1) i.p.).Conclusions and Implications:These data indicate that dysfunctions of neuronal K(v)7 channels deserve attention in dyskinesias [2].
• By contrast, retigabine and flupirtine (each at 10 microM) were less effective in counteracting NMDA- or OGD-induced toxicity in the CA1 region [3].
• The neuroprotective effects of i.c.v. injections of caspase inhibitors and systemic injections of the anticonvulsant drugs (AEDs) dizocilpine and retigabine after the status epilepticus were studied [4].
• Since the function of this channel is reduced in a hereditary epilepsy syndrome, retigabine may be the first anticonvulsant to directly target the deficit observed in a channelopathy [5].

Psychiatry related information on C13826

• In L5-ligated rats retigabine significantly and dose-dependently elevated the pain threshold and prolonged the withdrawal latency after tactile and thermal stimulation, respectively [6].
• Retigabine also has neuroprotective activity with potential for the treatment of stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and multiple sclerosis [249381] [7].

High impact information on C13826

• BACKGROUND: The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels [1].
• OBJECTIVE: Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retigabine [1].
• Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion [1].
• Consistent with its known action on potassium channels, retigabine significantly hyperpolarized the resting membrane potentials of the neurons, decreased input resistance, and decreased the number of action potentials generated by direct current injection [8].
• Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission [8].

Chemical compound and disease context of C13826

• Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dt (sz) mutant suggests that neuronal K(v)7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias [2].
• The anticonvulsant activity of the novel drug D-23129 (N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester) was evaluated in animal models of epileptic seizures [9].
• The spectrum of activity of retigabine resembles that of valproate, but its potency is greater and toxicity is reduced [373379] [7].

Biological context of C13826

• Retigabine also had a marked effect on KCNQ current kinetics, increasing the rate of channel activation but slowing deactivation at a given test potential [10].
• Interestingly, retigabine (0.01-10 microM) and flupirtine (0.01-10 microM) dose-dependently prevented DG neuronal death induced by SW, with IC50 s of 0.4 microM and 0.7 microM, respectively [3].
• METHODS: The proconvulsant effects of the M-channel blocker linopirdine (LPD) and anticonvulsant effects of the M-channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J-Szt1/+ (Szt1) and littermate control C57BL/6J+/+ (B6) mice [11].
• Injection of dizocilpine and to a lower extent also of retigabine after the status prevented limbic neurodegeneration and expression of markers of apoptosis [4].
• Urodynamic effects of the K+ channel (KCNQ) opener retigabine in freely moving, conscious rats [12].

Anatomical context of C13826

• It has recently been reported that retigabine modulates a potassium channel current in nerve growth factor-differentiated PC12 cells (), however, to date the molecular correlate of this current has not been identified [10].
• Application of 10 microM retigabine to oocytes expressing the KCNQ2/3 heteromeric channel shifted both the activation threshold and voltage for half-activation by approximately 20 mV in the hyperpolarizing direction, leading to an increase in current amplitude at test potentials between -80 mV and +20 mV [10].
• Retigabine (0.1 to 10 microM) induced a potassium current and hyperpolarized CHO cells expressing KCNQ2/Q3 cells but not in wild-type cells [13].
• The antiepileptic properties of retigabine were evaluated as effect on the frequency and amplitude of the epileptiform activities as well as time of onset of the effect in the entorhinal cortex (EC) and in hippocampal area CA1 (CA1) by using extracellular recording techniques [14].
• Other effects of retigabine were (1) increase in stimulation threshold; (2) increase in size of responses to suprathreshold stimuli; and (3) increase in amplitude and decrease in frequency of spontaneous dorsal root potentials [15].

Associations of C13826 with other chemical compounds

• In differentiated PC12 cells, retigabine enhanced a linopirdine-sensitive current [13].
• PURPOSE: Retigabine is a novel anticonvulsant drug that not only augments gamma-aminobutyric acid mechanisms, but also opens voltage gated K+ channels (KCNQ) [12].
• The aim of this study was to characterize bupivacaine effects on KCNQ2/Q3 channels and to investigate whether retigabine reverses the effects of the local anesthetic [16].
• CONCLUSIONS: Retigabine given intravenously, intracerebroventricularly and intravesically increased micturition volume and voiding intervals and, when given intravesically, it decreased capsaicin induced detrusor overactivity, suggesting that KCNQ channels can be interesting targets for drugs aiming at micturition control [12].
• 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 [17].

Gene context of C13826

• Using the differential sensitivity of KCNQ3 and KCNQ1 to retigabine, we constructed chimeras to identify minimal segments required for sensitivity to the drug [18].
• In the present study we have examined the effects of retigabine on recombinant human KCNQ2 and KCNQ3 potassium channels, expressed either alone or in combination in Xenopus oocytes [10].
• These findings identify KCNQ5/Q3 channels as a molecular target for retigabine and raise the possibility that activation of KCNQ5/Q3 channels may be responsible for some of the anti-convulsant activity of this agent [19].
• In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also [20].
• The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine [21].

Analytical, diagnostic and therapeutic context of C13826

• Because the heteromeric KCNQ2/3 channel has recently been reported to underlie the M-current, it is likely that M-current modulation can explain the anticonvulsant actions of retigabine in animal models of epilepsy [10].
• The whole-cell patch-clamp technique was used to examine the effects of retigabine, a novel anticonvulsant drug, on the electroresponsive properties of individual neurons as well as on neurotransmission between monosynaptically connected pairs of cultured mouse cortical neurons [8].
• The efficacy of retigabine is currently being tested in multicenter clinical trials; identification of its molecular targets will allow it to be more efficiently exploited as a "lead compound." Cloned human KCNQ channels can now be expressed in cultured cells for "high-throughput" screening of drug candidates [22].
• Retigabine is a compound of potential interest in analgesia which acts as an M-channel opener to depress neuronal excitability [15].
• Furthermore, newly discovered genes may be suitable as novel targets for pharmacotherapy such as KCNQ channels for the anticonvulsant drug retigabine [23].

References