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.