RT Journal Article
SR Electronic
T1 Pharmacological Activity and Safety Profile of P10358, a Novel, Orally Active Acetylcholinesterase Inhibitor for Alzheimer’s Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 710
OP 720
VO 280
IS 2
A1 Craig P. Smith
A1 Gina M. Bores
A1 Wayne Petko
A1 Mary Li
A1 David E. Selk
A1 Douglas K. Rush
A1 Fernando Camacho
A1 James T. Winslow
A1 Rod Fishkin
A1 Dana M. Cunningham
A1 Karen M. Brooks
A1 Joachim Roehr
A1 Harold B. Hartman
A1 Larry Davis
A1 Hugo M. Vargas
YR 1997
UL http://jpet.aspetjournals.org/content/280/2/710.abstract
AB 1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro(IC50 = 0.10 ± 0.02 μM vs. IC50 = 0.25 ± 0.03 μM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 ± 0.05 μM vs. IC50 = 0.07 ± 0.01 μM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/kg, it produced profound and long-lasting hypothermia in mice. P10358 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 elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 μM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer’s disease. The American Society for Pharmacology and Experimental Therapeutics