Enzyme inhibitor
This long-acting AChE inhibitor and A?42-lowering agent (FW = 337,42
g/mol; CAS 101246-66-6), also known as (–) -N-phenylcarbamoyl eseroline,
is a carbamate analogue of eserine (or physostigmine) that inhibits
acetylcholinesterase and is under active investigation for its potential in
cholinomimetic therapy to reduce cognitive impairments associated with
aging and Alzheimer's Disease. Phenserine is a potent and highly selective
AChE inhibitor (IC50 = 22 nM), displaying 70x greater inhibitory action
than observed with butyrylcholinesterase, or BChE (IC50 = 1560 nM), both
in vitro and in clinical trials for treatment of Alzheimer's disease (1-5).
Compared to physostigmine and tacrine, phenserine appears to be less toxic
and robustly enhances cognition in animal models. In rats, phenserine
achieves maximum acetylcholinesterase inhibition of 73.5% at 5 min,
maintaining high and relatively constant inhibition for >8 hours.
Phenserine decreased the levels of secreted b-amyloid precursor protein (b-
APP) in the cerebrospinal fluid (CSF) of forebrain cholinergic system-
lesioned rats, whereas DFP, a relatively non-specific cholinesterase
inhibitor, failed to affect CSF levels of secreted b-APP. Such findings
suggest that phenserine alters the induction of cortical b-APP mRNAs and
increased levels of secreted b-APP in the CSF. Phenserine reduces Ab
levels by regulating b-APP translation via a recently described iron
regulatory element in the 5'-untranslated region of b-APP mRNA that was
previously shown to be up-regulated in the presence of interleukin-1.
Other dual AChE/A?42 inhibitors include: rivastigmine, ladostigil,
asenapine, phenserine, amitriptyline, clomipramine, doxepin and
desipramine. Posiphen, the better-tolerated (+) -enantiomer of phenserine, is
devoid of anticholinesterase action, but represses translation of neural α-
synuclein, a druggable target in the treatment of Parkinson Disease.
