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PubMed2003

Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors.

Ambenonium (1), an old AChE inhibitor, is endowed with an outstanding affinity and a peculiar mechanism of action that, taken together, make it a very promising pharmacological tool for the treatment of Alzheimer's disease (AD). Unfortunately, the bisquaternary structure of 1 prevents its passage through the blood brain barrier. In a search of centrally active ambenonium derivatives, we planned to synthesize tertiary amines of 1, such as 2 and 3. In addition, to add new insights into the binding mechanism of the inhibitor, we designed constrained analogues of ambenonium by incorporating the diamine functions into cyclic moieties (4-12). The biological evaluation of the new compounds has been assessed in vitro against human AChE and BChE. All tertiary amine derivatives resulted more than 1000-fold less potent than 1 and, unlike prototype, did not show any selectivity between the two enzymes. This result, because of recent findings concerning the role of BChE in AD, makes our compounds, endowed with a well-balanced profile of AChE/BChE inhibition, valuable candidates for further development. To better clarify the interactions that account for the high affinity of 1, docking simulations and molecular dynamics studies on the AChE-1 complex were also carried out.

Acetylcholinesterase↗
PubMed2001

Reversible and irreversible acetylcholinesterase inhibitors cause changes in neuronal amyloid precursor protein processing and protein kinase C level in vitro.

The alternative routes of cleavage of the amyloid precursor protein (APP) result in the generation and secretion of both soluble APP and beta-amyloid, the latter being the main component of the amyloid deposits in the brains of individuals with Alzheimer's disease (AD). This study examined the question of whether acetylcholinesterase (AChE) inhibitors can alter the processing of APP and the level of protein kinase C (PKC) in primary rat basal forebrain cultures. Western blotting was used to test two AChE inhibitors (reversible and irreversible) for their ability to enhance the release of APP and PKC content. These inhibitors were ambenonium (AMB) and metrifonate (MTF), at different concentrations. A significant increase was found in the cell-associated APP level in a basal forebrain neuronal culture, and there was an elevation of the APP release into the medium. Increases were similarly observed in the PKC levels after AMB or MTF treatment. The results suggest that these AChE inhibitors promote the non-amyloidogenic route of APP processing, which may be due to their stimulatory effects on PKC. The PKC activation may enhance the alpha-secretase activity and consequently the production of the N-terminal APP. Since both a decreased level of APP secretion and a low activity and level of PKC may be involved in the pathogenesis of AD, it is concluded that the administration of AChE inhibitors to AD patients may facilitate the memory processes and exert a neuroprotective effect.

Ambenonium Chloride↗
PubMed1988

Determination of ambenonium in biological samples by reversed-phase ion-pair liquid chromatography.

A sensitive and selective analytical method for the determination of ambenonium ion in biological samples is described. The procedure involves ion-pair extraction of the drug, followed by reversed-phase ion-pair chromatographic analysis with ultraviolet detection at 217 nm. The detection limits at a signal-to-noise ratio of 5 were 100 pmol/ml using 0.2 ml of plasma and bile, 250 pmol/ml using 0.2 ml of urine and 200 pmol/g using 1 ml of tissue homogenates containing 0.1 g/ml of each tissue. This assay procedure was used to study the pharmacokinetics of ambenonium ion after intravenous administration in rats.

Ambenonium Chloride↗
PubMed2001

Thyroid gland tumour, pemphigus foliaceus and myasthenia gravis in the daughter of a woman with myasthenia gravis.

We describe a rare case of pemphigus foliaceus associated with familial myasthenia gravis (MG). A 35-year-old woman developed MG during oral corticosteroid treatment for pemphigus foliaceus. She had been operated on for a thyroid gland tumour that was confirmed histopathologically to be papillary carcinoma without metastasis. At the time of treatment, her mother had had MG for 30 years and undergone thymectomy 22 years ago. A specific ELISA technique showed that antidesmoglein 1 antibody was present in the daughter. There are many reports of multiple diseases such as pemphigus, thymoma, malignancy, and other autoimmune diseases associated with MG. However, familial MG following pemphigus foliaceus has not been reported previously.

Adult↗
PubMed1977

The generation of nerve and muscle repetivie activity in the rat phrenic nerve-diaphragm preparation following inhibition of cholinesterase by ecothiopate.

1 Simultaneous extracellular recordings were made from two end-plate zones of the isolated diaphragm and from the phrenic nerve of the rat in response to stimulation of the nerve. The contractions of the diaphragm were also recorded.2 In the curarized diaphragm, the introduction of ecothiopate, a non-competitive inhibitor of cholinesterase, caused a threefold increase in the amplitude of the end-plate current and an eightfold increase in the duration at half the peak amplitude.3 In the non-curarized diaphragm, the introduction of ecothiopate caused the generation of repetitive activity (RA) in first the phrenic nerve: this was then followed by RA in the diaphragm. At that stage, nerve RA possessed a shorter latency than muscle RA. The generation time for nerve RA was 1.6 ms and for mRA, it was 2.7 milliseconds.4 Nerve RA was more labile than muscle RA; it was readily abolished by increasing the frequency of stimulation, by magnesium, by tubocurarine or by high concentrations of ecothiopate, whereas muscle RA was still generated. Steady exposure to acetylcholine abolished both forms of RA.5 Two competitive inhibitors of cholinesterase, neostigmine and ambenonium, were also shown to evoke RA in nerve and muscle. The generation times for nerve RA and muscle RA were similar to those following ecothiopate.6 It was concluded that nerve RA and muscle RA were generated after the inhibition of cholinesterase by ecothiopate as a result of the prolonged action of acetylcholine upon cholinoceptive sites on the nerve terminal and motor endplate respectively. A direct excitatory action of ecothiopate upon the phrenic nerve terminals was excluded.

Acetylcholine↗