Description
Linopirdine is an enhancer of the stimulus-evoked but not basal release of several neurotransmitters, including acetylcholine, dopamine, serotonin, and glutamate. It increases acetylcholine release in rat hippocampal CA1 neurons by blocking voltage-gated, calcium-activated and leak (M-type; K
v7.2/7.3; KCNQ2/3) K
+ current with an IC
50 value of 2.4 μM. Inhibition of M-channels is reported to result in the depolarization of CA3 pyramidal neurons and activated presynaptic voltage-gated P/Q- and N-type calcium channels, which leads to Ca
2+ influx and increased neurotransmitter release. Linopirdine has been shown to produce a number of effects including EEG patterns of enhanced vigilance, induction of c-fos expression in cerebral cortex, reduction of the increase of cerebral glucose utilization induced by hypoxia, and improved performance in animal models of learning and memory. Linopirdine has also been identified as an agonist of transient receptor potential vanilloid type 1 (EC
50 = 115 μM in HEK293 cells voltage clamped at -60 mV).
Uses
Alzheimer’s disease
treatment (cognition enhancer).
Definition
ChEBI: Linopirdine is a member of indoles.
Biological Activity
Blocker of KCNQ voltage-gated potassium channels; blocks KCNQ2+3/M-currents (IC 50 = 4-7 μ M) and KCNQ1 homomeric channels (IC 50 = 8.9 μ M). Augments hippocampal ACh release and is a cognitive enhancer following oral administration in vivo .
in vivo
Linopirdine (DuP 996; i.v.; 0.1-6 mg/kg; increasing doses) transiently (10-15 min) and dose-dependently increases MAP by up to 15%[2].
| Animal Model: | Male Sprague-Dawley rats (300-350 g)[2] |
| Dosage: | 0.1, 0.5, 1, 3, 6 mg/kg |
| Administration: | 5 intravenous bolus injections of increasing doses |
| Result: | Transiently and dose-dependently increases MAP by up to 15%.
|
References
[1] M E SCHNEE B S B. Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.[J]. Journal of Pharmacology and Experimental Therapeutics, 1998, 286 2: 709-717.
[2] DORIS KRISTUFEK. Modulation of Spontaneous and Stimulation-Evoked Transmitter Release from Rat Sympathetic Neurons by the Cognition Enhancer Linopirdine: Insights into Its Mechanisms of Action[J]. Journal of Neurochemistry, 2008, 72 5: 2083-2091. DOI:
10.1046/j.1471-4159.1999.0722083.x[3] JIANLI SUN Jaideep K. M-type potassium channels modulate Schaffer collateral–CA1 glutamatergic synaptic transmission[J]. Journal of Physiology-London, 2012, 590 16: 3953-3964. DOI:
10.1113/jphysiol.2012.235820[4] S W TAM R Z. Linopirdine. A depolarization-activated releaser of transmitters for treatment of dementia.[J]. Advances in experimental medicine and biology, 1995, 363: 47-56.
[5] CRISTIAN NEACSU Alexandru B. The M-Channel Blocker Linopirdine Is an Agonist of the Capsaicin Receptor TRPV1[J]. Journal of pharmacological sciences, 2010, 114 3: Pages 332-340. DOI:
10.1254/jphs.10172fp
