PHARMACOLOGICAL ACTIVITY AND SAFETY PROFILE OF P10358, A NOVEL, ORALLY-ACTIVE ACETYLCHOLINESTERASE INHIBITOR FOR ALZHEIMERS-DISEASE

Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P 10358) is a potent, reversible acetylcholinesterase inhibitor that pro duces central cholinergic stimulation after oral and parental administ ration in rats and mice. P10358 is a 2.5 times more potent acetylcholi nesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 mu M vs. I C50 = 0.25 +/- 0.03 mu M). It also inhibits butyrylcholinesterase acti vity as potently as THA (IC50 = 0.08 +/- 0.05 mu M vs. IC50 = 0.07 +/- 0.01 mu M). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-depe ndent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/kg, it produced profound and long-lasting hypothermia in mice. P103 58 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose e levated striatal homovanillic acid levels. These behavioral and bioche mical effects are consistent with central cholinergic stimulation. Hem odynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arteria l pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 8 0 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindol e and may not have the hepatotoxic liability associated with aminoacri dine structure of tacrine. P10358 had weak affinity (> 10 mu M) at a v ariety of aminergic and peptidergic receptors and uptake carriers. The se properties suggest that P10358 may be a safe and promising symptoma tic treatment for Alzheimer's disease.