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.

Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine.

Linopirdine (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, DUP996) is an extensively studied representative of a class of cognition enhancing compounds that increase the evoked release of neurotransmitters. Recent studies suggest that these agents act through the blockade of specific K+ channels. We have recently identified more potent anthracenone analogs of linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991) and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although linopirdine possesses an EC50 of 4.2 microM for enhancement of [3H]ACh release from rat brain slices, XE991 and DMP 543 have EC50S of 490 and 700 nM, respectively. In addition to greater in vitro potency relative to linopirdine, both compounds show greater in vivo potency and duration of action. Although 5 mg/kg (p.o.) linopirdine does not lead to statistically significant increases in hippocampal extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to increases (maximal effect > 90% over baseline) which are sustained for 60 min. Moreover, DMP 543 at 1 mg/kg causes more than a 100% increase in acetylcholine levels with the effect lasting more than 3 hr. At doses relevant to their release-enhancing properties, the only overt symptom consistently observed was tremor, possible via a cholinergic mechanism. These results suggest that XE991 and DMP 543 may prove to be superior to linopirdine as Alzheimer's disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the importance of particular ion channels in the control of neurotransmitter 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.