Disease relevance of C13780

• To determine the pathological consequences of the inhibition of cochlear KCNQ channels, we developed a hearing loss model based on a chronic intracochlear perfusion of linopirdine via an osmotic minipump [1].
• Since linopirdine protects against hypoxia-induced passive avoidance deficits in rats, we also examined the effects of linopirdine on cerebral metabolism after the rats were exposed to 30 min of hypoxia [2].
• Rats treated with linopirdine showed ptosis, salivation, slight sedation, paw beating and slight hypothermia [3].

Psychiatry related information on C13780

• Thirty-five patients with probable Alzheimer's disease who were enrolled in an experimental drug trial of linopirdine underwent repeated testing that included recording the middle latency auditory evoked potential (MLAEP), the Mini-Mental State Examination (MMSE), and the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADASCOG) [4].
• Linopirdine is a compound being assessed for value in reversing the dementia associated with Alzheimer's disease [5].
• In acute behavioral experiments, MKC-231 and THA had no significant effect on AF64A-induced memory deficits at any doses tested (0.3, 1.0 and 3.0 mg/kg), whereas Dup 996, at a dose of 1.0 mg/kg, significantly improved memory deficits [6].
• In the CRF task, linopirdine did not affect the response latency and the 24-h retention of young rats [7].
• In this study, sound sequence discrimination learning attenuated by 192IgG-saporin was also restored by linopirdine [8].

High impact information on C13780

• Retigabine-induced currents in CHO-KCNQ2/Q3 cells were inhibited by 60.6 +/- 11% (n = 4) by the KCNQ2/Q3 blocker, linopirdine (10 microM), and 82.7 +/- 5.4% (n = 4) by BaCl(2) (10 mM) [9].
• In voltage-clamp experiments using large myelinated fibres, the selective KCNQ channel blockers XE991 (IC50 = 2.2 microm) and linopirdine (IC50 = 5.5 microm) completely inhibited I(Ks), as did TEA (IC50 = 0.22 mm) [10].
• In contrast, in aged rats linopirdine caused widespread expression of Fos throughout neocortex [11].
• Modulation of spontaneous and stimulation-evoked transmitter release from rat sympathetic neurons by the cognition enhancer linopirdine: insights into its mechanisms of action [12].
• Furthermore, linopirdine potently targets nAChRs to modulate stimulus-secretion coupling in adrenal chromaffin cells [13].

Biological context of C13780

• Current clamp experiments in the perforated-patch configuration showed XE991 and linopirdine depolarised the resting membrane potential and augmented the evoked response in a concentration-dependent manner [14].
• The concomitant decrease in cochlear microphonic potential and distortion product otoacoustic emission amplitude indicates that linopirdine has an effect on the outer hair cells (OHCs) [1].
• When perfused into intact cochlea, linopirdine transiently increases the summating potential and endocochlear potential, suggesting that it alters K+ homeostasis [1].
• Competition experiments showed that [(3)H]linopirdine is displaced by unlabelled linopirdine with comparable affinities from its binding sites on rat brain and rat liver membranes [15].
• Single-dose pharmacokinetics, safety, and tolerance of linopirdine (DuP 996) in healthy young adults and elderly volunteers [16].

Anatomical context of C13780

• The mechanisms by which the cognition enhancer linopirdine may affect transmitter release were investigated in cultures of rat superior cervical ganglion neurons [12].
• Linopirdine (10 microM) reduced inward currents through the low-voltage-activated K(+) current in type I hair cells, but concentrations up to 200 microM had little effect on steady-state outward K(+) current in these cells [17].
• The present study examines the possible involvement of channels which mediate the movement of K+, Cl- and Na+, which are important to the polarization state of excitable membranes, in the release-enhancing effects of linopirdine [5].
• The mechanism involved in the blockade of M-current by linopirdine was studied in cultured rat superior cervical sympathetic ganglia using whole-cell patch clamp recording [18].
• Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction [19].

Associations of C13780 with other chemical compounds

• In this study we have monitored by Fos immunohistochemistry the effect of the acetylcholine release enhancer linopirdine (DUP996) on the immediate early gene c-fos in brains of 3 months and 30 months old rats [11].
• The M-current blockers, linopirdine (DuP 996; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) and XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), inhibited the activation of the KCNQ5 channel induced by the BMS-204352 [20].
• The voltage-independent current reversed at the equilibrium potential for potassium ( E(K)), hence was carried by a K+ conductance, and was blocked by the selective KCNQ channel blockers XE991 and linopirdine [21].
• Furthermore, apamin and paxilline, specific blockers of Ca(2+)-activated SKand BK-type K(+) channels, respectively; E-4031, a blocker of ether a-go-go K(+) channel; and linopirdine, a blocker of M-type K(+) channel, did not affect the agonist-specific patterns of calcium signaling and PRL secretion [22].

Gene context of C13780

• The KCNQ4 channels were blocked in a voltage-independent manner by the memory-enhancing M current blockers XE-991 and linopirdine with IC(50) values of 5.5 and 14 microM, respectively [23].
• Furthermore, the sensitivity of KCNQ5/Q3 channels to linopirdine supports the possibility that potassium channels comprised of KCNQ5 and KCNQ3 may make a contribution to native M-currents [24].
• This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine [25].
• Linopirdine, a tool useful in targeting native or heterologous KCNQ channels, was used to study the role of KCNQ channels in the guinea pig cochlea [1].
• CYP induction increased the metabolism of linopirdine [26].

Analytical, diagnostic and therapeutic context of C13780

• RESULTS: Bath perfusion of linopirdine induced epileptiform activity only in slices from neonatal rats [27].
• Our study examines the selectivity of linopirdine for IM by determining its effects on other ionic currents present in rat hippocampal CA1 neurons using patch clamp techniques [28].
• Inhibitors of M-channels, such as linopirdine and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991), enhance depolarization-induced transmitter release and improve learning performance in animal models [29].
• The subjects who received linopirdine did not experience clinically important changes in vital signs, electrocardiograms (ECGs), electroencephalograms (EEGs), or clinical laboratory evaluations [16].
• Linopirdine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection [16].

References