Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease.

Abstract	A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.
Authors	Yasuyuki Abe, Atsushi Aoyagi, Takao Hara, Kazumi Abe, Reina Yamazaki, Yoshihiro Kumagae, Shunji Naruto, Kazuo Koyama, Shinji Marumoto, Keiko Tago, Narihiro Toda, Kazuko Takami, Naho Yamada, Mayuko Ori, Hiroshi Kogen, Tsugio Kaneko
Journal	Journal of pharmacological sciences (J Pharmacol Sci) Vol. 93 Issue 1 Pg. 95-105 (Sep 2003) ISSN: 1347-8613 [Print] Japan
PMID	14501158 (Publication Type: Comparative Study, Journal Article)
Chemical References	4-((1S)-methylamino-3-(4-nitrophenoxy))propylphenyl N,N-dimethylcarbamate Carbamates Carrier Proteins Cholinesterase Inhibitors Fumarates Membrane Glycoproteins Membrane Transport Proteins Nerve Tissue Proteins Serotonin Plasma Membrane Transport Proteins Slc6a4 protein, mouse Slc6a4 protein, rat Acetylcholinesterase
Topics	Acetylcholinesterase (metabolism) Administration, Oral Aging (drug effects, physiology) Alzheimer Disease (drug therapy, metabolism) Animals Carbamates (chemistry, pharmacology, therapeutic use) Carrier Proteins (antagonists & inhibitors, physiology) Cholinesterase Inhibitors (chemistry, pharmacology, therapeutic use) Fumarates (chemistry, pharmacology, therapeutic use) Hippocampus (drug effects, enzymology, metabolism) Male Maze Learning (drug effects, physiology) Membrane Glycoproteins (antagonists & inhibitors, physiology) Membrane Transport Proteins Memory (drug effects, physiology) Mice Microdialysis Motor Activity (drug effects, physiology) Nerve Tissue Proteins (antagonists & inhibitors, physiology) Rats Rats, Inbred F344 Rats, Sprague-Dawley Rats, Wistar Serotonin Plasma Membrane Transport Proteins

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