TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 724 LP - 730 VL - 285 IS - 2 AU - R. Zaczek AU - R. J. Chorvat AU - J. A. Saye AU - M. E. Pierdomenico AU - C. M. Maciag AU - A. R. Logue AU - B. N. Fisher AU - D. H. Rominger AU - R. A. Earl Y1 - 1998/05/01 UR - http://jpet.aspetjournals.org/content/285/2/724.abstract N2 - 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 μM 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 vivopotency 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. The American Society for Pharmacology and Experimental Therapeutics ER -