Abstract
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.
Footnotes
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Send reprint requests to: Dr. Craig P. Smith, Hoechst Marion Roussel, Inc., Neuroscience TD, PO Box 6800, Routes 202–206, Bridgwater, NJ 08807-0800.
- Abbreviations:
- AChE
- acetylcholinesterase
- AChEI
- acetylcholinesterase inhibitor
- AD
- Alzheimer’s disease
- BuChE
- butyrylcholinesterase
- DA
- dopamine
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- HEP
- heptylphysostigmine
- HVA
- homovanillic acid
- NE
- norepinephrine
- P10358
- 1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate
- SCOP
- scopolamine hydrobromide
- 5-HT
- serotonin
- THA
- tacrine
- TRANYLCYP
- tranylcypromine
- MAP
- mean arterial pressure
- HR
- heart rate
- LSD
- least significant difference
- Received May 6, 1996.
- Accepted October 25, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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