2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action.

In an effort to improve the pharmacokinetic and pharmacodynamic properties of the cognition-enhancer linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant group was systematically replaced with 2-fluoro-4-pyridyl. This strategy resulted in the discovery of several compounds with improved activity in acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, 10, 10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In addition to superior potency, 9 possesses an improved pharmacokinetic profile compared to that of linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of linopirdine (0.5 h), and it showed a 6-fold improvement in brain-plasma distribution over linopirdine. On the basis of its pharmacologic, pharmacokinetic, absorption, and distribution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's disease.

Unique properties of norepinephrine release from terminals arising from the locus coeruleus: high potassium sensitivity and lack of linopirdine (DuP 996) enhancement.

The dose-response of K+ to elicit the release of norepinephrine (NE), acetylcholine (ACh), dopamine (DA) and serotonin (5-HT) from rat brain slices was examined. Cerebral cortical and hippocampal [3H]NE release had steeper K+ dose-response curves than those observed for apparent hippocampal [3H]ACh, striatal [3H]DA and striatal [3H]5-HT release. In contrast, the apparent release of [3H]NE from the hypothalamus had a K+ dose-response curve similar to those observed for the release of [3H]ACh, [3H]DA and [3H]5-HT. Linopirdine, a drug which enhances K(+)-stimulated release of [3H]Ach, [3H]DA and [3H]5-HT, had no effect on cerebral cortical [3H]NE release even at submaximal K+ stimulation. Hippocampal [3H]NE release was also not affected by linopirdine, however the compound significantly enhanced K(+)-evoked [3H]NE release from hypothalamic slices. These data point to unique properties of [3H]NE release from terminals arising from the locus coeruleus (i.e. those found in the cerebral cortex and hippocampus) when compared to [3H]NE release from terminals derived from the lateral tegmentum (i.e. those found in the hypothalamus) and the release properties of other neurotransmitters. The relative high K+ sensitivity of NE release from coerulear terminals may be related to the lack of linopirdine effects on cerebral cortical and hippocampal [3H]NE release.

Studies on the role of K+, Cl- and Na+ ion permeabilities in the acetylcholine release enhancing effects of linopirdine (DuP 996) in rat cortical slices.

Linopirdine is a compound being assessed for value in reversing the dementia associated with Alzheimer's disease. The drug improves learning and memory performance in several rodent behavioral paradigms. Its proposed mechanism of action is the enhancement of neurotransmitter release, but the molecular site which mediates this action is unknown. 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. Linopirdine causes a shift in the K+ dose response for the release of tritium from cerebral cortical slices preloaded with [3H]choline ([3H]acetylcholine (ACh) released) to the left, consistent with the blockade of a site, such as a K+ channel, involved in dampening the response of neuronal terminals to depolarizing stimuli. Linopirdine does not appear to act at aminopyridine-sensitive K+ channels, inasmuch as the aminopyridines and linopirdine have different patterns of effects regarding [3H]ACh release. Tetraethylamonium (TEA), on the other hand, does share common effects with linopirdine. TEA enhances K(+)-evoked [3H]ACh release to as much as 620% of control without affecting basal efflux of the neurotransmitter. Experiments using the muscarinic agonist carbachol indicate that linopirdine does not affect the cholinergic autoreceptor influence on [3H]ACh release. Linopirdine also does not appear to act at tetrodotoxin-sensitive Na+ channels. The anion channel blocker 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid and Cl(-)-deficient media do not affect the level of linopirdine release enhancement.