Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 280; no. 2; pp. 710 - 720
• Main Authors: Smith, C P, Bores, G M, Petko, W, Li, M, Selk, D E, Rush, D K, Camacho, F, Winslow, J T, Fishkin, R, Cunningham, D M, Brooks, K M, Roehr, J, Hartman, H B, Davis, L, Vargas, H M
• Format: Journal Article
• Language: English
• Published: United States 01.02.1997
• Subjects: Acetylcholinesterase - metabolism; Administration, Oral; Alzheimer Disease - drug therapy; Aminopyridines - administration & dosage; Aminopyridines - therapeutic use; Aminopyridines - toxicity; Animals; Avoidance Learning - drug effects; Brain - drug effects; Brain - metabolism; Butyrylcholinesterase - metabolism; Carbamates - administration & dosage; Carbamates - therapeutic use; Carbamates - toxicity; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - therapeutic use; Cholinesterase Inhibitors - toxicity; Corpus Striatum - metabolism; Dopamine - metabolism; Female; Humans; Hypothermia, Induced; Kinetics; Male; Maze Learning - drug effects; Memory; Mice; Mice, Inbred Strains; Ovariectomy; Prosencephalon - enzymology; Rats; Rats, Wistar; Scopolamine Hydrobromide - pharmacology; Social Behavior; Space Perception; Time Factors
• ISSN: 0022-3565

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 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). 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 microM) 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.