2 NEW POTENT NEUROTRANSMITTER RELEASE ENHANCERS, 10,10-BIS(4-PYRIDINYLMETHYL)-9(10H)-ANTHRACENONE AND IS(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 enha ncing 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 anthrace none analogs of linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthr acenone (XE991) and is(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although linopirdine possesses an EC50 of 4.2 mu M for enh ancement of [H-3]ACh release from rat brain slices, XE991 and DMP 543 have EC(50)s of 490 and 700 nM, respectively. In addition to greater i n vitro potency relative to linopirdine, both compounds show greater i n vivo potency and duration of action. Although 5 mg/kg (p.o.) linopir dine does not lead to statistically significant increases in hippocamp al extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to i ncreases (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 dos es relevant to their release-enhancing properties, the only overt symp tom consistently observed was tremor, possible via a cholinergic mecha nism. These results suggest that XE991 and DMP 543 may prove to be sup erior to linopirdine as Alzheimer's disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the i mportance of particular ion channels in the control of neurotransmitte r release.