Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carbamate 1-(methyl-3-(N,N-dimethylcarbamoyloxy)-2-pyridylmethylene)-4 -(4-phenyl) diazinecarboxamide chloride (MHP 133) is the parent for a new class of pyridinium salts which inhibit acetylcholinesterase (AChE) in vitro as well as in vivo. Fourteen new derivatives of MHP 133 have been synthesized with the intention of improving their hydrophobicity while maintaining their propensity to inhibit acetylcholinesterase. Upon prolonged incubation with AChE, the pyridinium salts exhibit progressive time-dependent inhibition according to first order kinetics with kobs/[I] values ranging from 3 to 345 M-1s-1. The enzyme did not regain any activity after prolonged incubation with the inhibitors (1 day). The partition coefficients for each inhibitor were evaluated in octanol/water in order to determine their hydrophobic character as hydrophobicity is a key prerequisite for crossing the blood brain barrier.
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PMID:Novel pyridinium derivatives as inhibitors for acetylcholinesterase. 883 28

MHP-133 is one of a novel series of compounds designed to target multiple brain substrates expected to have synergistic actions in the treatment of cognitive and neurodegenerative disorders such as Alzheimer's disease. The strategy was to develop compounds with multiple targets relevant for enhancing cognition and memory, but avoiding the serious side effects attributed to high potency cholinergic agonists. MHP-133 was shown to interact with subtypes of cholinergic, serotonergic, and imidazoline receptors and to weakly inhibit acetylcholinesterase activity. In vitro, the drug enhanced nerve growth factor (TrkA) receptor expression; it prevented excitotoxicity in a hippocampal slice preparation; and increased the secretion of soluble (non-toxic) amyloid precursor protein. MHP-133 also enhanced cognitive performance by rats and by non-human primate in tasks designed to assess working memory. The results of this study are consistent with the potential use of MHP-133 in the treatment of neurodegenerative disorders such as Alzheimer's disease.
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PMID:MHP-133, a drug with multiple CNS targets: potential for neuroprotection and enhanced cognition. 1740 38