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Linopirdine is a putative cognition-enhancing drug with a novel mechanism of action. Linopirdine blocks the KCNQ2\3 heteromer M current with an IC50 of 2.4nM disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons. In a murine model linopirdine is able to nearly completely reverse the senescence-related decline in cortical c-FOS, an effect which is blocked by atropine and MK-801, suggesting Linopirdine can compensate for the age related decline in acetylcholine release. Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3.

Cognitive Enhancement
Linopirdine was originally conceived as a cognitive enhancer. In rat models, the drug was shown to increase extracellular cortical levels of ACh release in in vivo models. At low doses, the drug was shown to increase cognitive and mnemonic function in rats performing an avoidance task. Rats primed with linopirdine prior to an avoidance trial performed better in the trials following priming. In rat models, linopirdine improved cognitive function, as shown by the improvement in avoidance task this could be applicable in humans. In rat models, it is effective at low doses in task acquisition and consolidation of information. However, at high doses, linopirdine has little to no effect. One mode of action that has been suggested as a pathways of neurocognitive enhancement is the effect of linopirdine on neuritic branching. Linopirdine increase the number of neurites per cell in cultured embryonic hippocampal neurons after 3 days. This increase in neuritic branches could indicate an increase in synaptic contacts which may have the effect of slowing or reversing the loss of function associated with neuronal trauma of disease.

Alzheimer's Disease
Originally tested for its use as a neurocognitive enhancer, linopirdine was eventually tested for its efficacy in the possible treatment of Alzheimer's disease, a common form of demential for which there is no cure. One of the existing hypothesis on the cause of Alzheimer's is the cholinergic hypothesis. At the core of the cholinergic hypothesis is there there is a substantial presynaptic cholinergic deficit. Recent studies have come out since the initial cholinergic hypothesis challenging the veracity of the hypothesis. Other systems other than the cholinergic system have been implicated in the cognitive decline seen in AD. The most common target of AD treatment has then been at cholinergic activity in the central nervous system. Attempts to treat AD by stimulating the cholinergic systems has been met with moderate success. Linopirdine was found to increase the release of ACh and other neurotransmitters as mediated by the high potassium concentration. Linopirdine not only enhances ACh release but also enhances the release of glutamate, dopamine, aspartate, GABA and serotonin as shown in in vitro rat brain slices. This is particularly important in the treatment of AD because of its pathology in several systems. Treatment with linopirdine and a placebo in a randomized trial showed no effects from the linopirdine

Method of Action
The exact site of action of linopirdine is not yet known however, findings indicate a novel site of action for the drug. Studies have looked at the effects on linopirdine on ion channels. It's effects were found to be insensitive to 4-aminopyridine, atropine and Na+, Cl− and Ca2+channel antagonists. The most promising evidence of action via ion channels was found when TEA was administered. A potassium channel blocker, TEA has similar action to that of linopirdine on ACh in the use of potassium channels. It has been suggested that the M-channel block may be the underlying mechanism of the linopirdine induced neurotransmitter release.

Route of Admission and Toxicity
In animal models, linopirdine was administered orally. During the cognitive enhancement tests in humans, the drug was administered orally as well. Linopirdine has a low toxicity which is one of the reasons it is appealing as a treatment option for AD. The volume of distribution for linopirdine in human plasma is 2.5ng/mL and 10.0 ng/mL after a 40 mg oral dosage to elderly patients. Urinary excretion of linopirdine was found to be negligible. There is little knowledge on the side effects of linopirdine as the studies on the drug appear to be discontinued.