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Pharmacological Characterization of RS-1259, an Orally Active Dual Inhibitor of Acetylcholinesterase and Serotonin Transporter, in Rodents: Possible Treatment of Alzheimer’s Disease

Authors :
Reina Yamazaki
Yasuyuki Abe
Shinji Marumoto
Naho Yamada
Kazuko Takami
Shunji Naruto
Takao Hara
Hiroshi Kogen
Keiko Tago
Tsugio Kaneko
Mayuko Ori
Narihiro Toda
Yoshihiro Kumagae
Kazuo Koyama
Kazumi Abe
Atsushi Aoyagi
Source :
Journal of Pharmacological Sciences, Vol 93, Iss 4, Pp 95-105 (2003)
Publication Year :
2003
Publisher :
Japanese Pharmacological Society, 2003.

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)1/2salt), 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 Alzheimers disease.

Details

ISSN :
13478648 and 13478613
Volume :
93
Database :
OpenAIRE
Journal :
Journal of Pharmacological Sciences
Accession number :
edsair.doi.dedup.....4b3bb34549738db235617f36457bc869
Full Text :
https://doi.org/10.1254/jphs.93.95