Long chain analogs of physostigmine as potential drugs for Alzheimer's disease: new insights into the mechanism of action in the inhibition of acetylcholinesterase

Perola, Emanuele; Cellai, Luciano; Lamba, Doriano; Filocamo, Luigi; Brufani, M.

doi:10.1016/s0167-4838(97)00133-7

Cited by 60 publications

(56 citation statements)

References 13 publications

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“…Other experimental methods used to calculate k diss values of ChE inhibitors included HPLC 20) and dialysis membranes. 19) The greatest advantage of the method used in the present study is that no special equipment such as an HPLC instrument is required. When compared to the method using dialysis membranes, the separation of unreacted ChE inhibitors from AChE in our study could be completed within a relatively short time (5 min) versus 24 h required for dialysis membrane methods.…”

Section: Discussionmentioning

confidence: 99%

“…1). Concerning this feature, Perola et al 19) have reported that the introduction of a long-chain alkyl group into physostigmine greatly reduced its k diss compared to that of the parent physostigmine. Perola et al 19) speculated that the introduction of a hydrophobic group prevents water molecules, which are needed for decarbamoylation, from accessing the AChE active site.…”

Section: Discussionmentioning

confidence: 99%

“…Concerning this feature, Perola et al 19) have reported that the introduction of a long-chain alkyl group into physostigmine greatly reduced its k diss compared to that of the parent physostigmine. Perola et al 19) speculated that the introduction of a hydrophobic group prevents water molecules, which are needed for decarbamoylation, from accessing the AChE active site. Therefore, the presence of a long-chain alkyl group in the distigmine molecule prevents the water moleculeinduced dissociation from AChE and thus, makes the dissociation time of distigmine 40-120 times longer than that of other ChE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The dissociation rate constant (k diss ) was obtained using the modified methods reported by Perola et al 19) and Bartolini et al,20) whose principles are described below. The reaction of AChE (EH) with a ChE inhibitor (AB) will produce a complex of AChE-ChE (EA) through an intermediate product (EH···AB) [reaction (5)]:…”

Section: Assessment Of Inhibitory Effects Of Ache Inhibitors On Ache mentioning

confidence: 99%

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Long-Lasting Inhibitory Effects of Distigmine on Recombinant Human Acetylcholinesterase Activity

Obara

Chino

Tanaka

2017

Biological & Pharmaceutical Bulletin

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To elucidate the mechanism whereby distigmine, an underactive bladder remedy, potentiates urinary bladder contractions long-lastingly, the inhibition of recombinant human acetylcholinesterase (rhAChE) by distigmine was investigated. A centrifugal ultrafiltration device, Nanosep ® 10K, was used to separate rhAChE and a bound inhibitor from an unbound inhibitor, reaction substrate, and reaction product. This allowed the same aliquot of rhAChE to be repeatedly assayed for up to 48 h to confirm the long-lasting binding of an inhibitor. Cholinesterase (ChE) inhibitors, distigmine, pyridostigmine, neostigmine, and ambenonium, were tested. The dissociation rate constant (k diss ) and dissociation half-life (t 1/2 ) of each inhibitor were determined based on the changes in rhAChE activity. Within 2-4 h after removing pyridostigmine, neostigmine, or ambenonium, the rhAChE activity was restored to the control levels. The k diss values for pyridostigmine, neostigmine, and ambenonium were calculated to be 0.51 0.05, 0.66 0.03, and 1.41 0.08 h 1 , and the t 1/2 values were calculated to be 1.36, 1.05, and 0.49 h, respectively. With distigmine, the rhAChE activity initially dropped to 17% of that in the control and then slowly recovered to only 50% by 48 h after drug removal. The k diss and t 1/2 values of distigmine were calculated to be 0.012 0.001 h 1 and 57.8 h, respectively. Based on the t 1/2 values, distigmine was judged to dissociate from acetylcholinesterase (AChE) 40-120-fold slower than the other ChE inhibitors did. This may explain the long-lasting potentiation of urinary bladder contractions and motility by distigmine as a treatment for an underactive bladder. Key words distigmine bromide; acetylcholinesterase; cholinesterase inhibitorDistigmine is a reversible cholinesterase (ChE) inhibitor from the class of carbamates. It was chemically synthesized by Schmid 1) and has a chemical structure consisting of two molecules of pyridostigmine connected by hexamethylene bonds (Fig. 1). Distigmine is used clinically in some Asian and European countries, including Japan and Germany, 2-8) and the main clinical indication for distigmine is myasthenia gravis.2,9) However, in Japan, distigmine has also been used for glaucoma 3) and an underactive bladder. 4-8)The effectiveness and usefulness of distigmine for underactive bladder treatment have been shown in many clinical studies. [4][5][6][7][8] However, the experimental evidence to support these clinical reports was not convincing. Therefore, our laboratory started pharmacological studies on the effects of distigmine on urinary bladder (UB) motility and has previously reported results supporting the clinical effectiveness and usefulness of distigmine. [10][11][12][13][14][15][16][17][18] The most remarkable pharmacological characteristic of distigmine was the persistence of its effect. In particular, distigmine was found to potentiate the UB internal pressure via the micturition reflex for more than 12 h. 17)Interestingly, the long-lasting potentiating effect of distigmine o...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Assessment Of Inhibitory Effects Of Ache Inhibitors On Ache mentioning

confidence: 99%

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Long-Lasting Inhibitory Effects of Distigmine on Recombinant Human Acetylcholinesterase Activity

Obara

Chino

Tanaka

2017

Biological & Pharmaceutical Bulletin

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“…Dissociation rate constants (k) were calculated as described by Perola et al 16) and Bartolini et al,17) with some modifications as described below.…”

Section: Drugs and Materialsmentioning

confidence: 99%

The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity

Obara

Ogawa

Chino

et al. 2017

Biological & Pharmaceutical Bulletin

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Distigmine bromide (distigmine), a reversible, long-lasting cholinesterase (ChE) inhibitor, is used for the treatment of underactive bladder in Japan and has been shown to potentiate urinary bladder (UB) contractility. We studied the duration of distigmine's potentiating effects on acetylcholine (ACh)-induced UB contraction and its inhibitory effects on ChE activity, and compared that with those of other ChE inhibitors (neostigmine, pyridostigmine, and ambenonium). The duration of potentiating/inhibitory effects of ChE inhibitors, including distigmine, on ACh-induced guinea pig UB contraction/ChE activity was evaluated for 12 h following washout. Dissociation rate constants (k) of the inhibitors were also tentatively calculated based on the time courses of their ChE inhibitory effects. The potentiating effect of distigmine (10 −6 M) on AChinduced UB contraction and its inhibitory effect on ChE activity were significantly sustained 12 h after washout. The potentiating effect of other ChE inhibitors on ACh-induced UB contraction, however, was sustained only until 3 h after washout. The ChE inhibitory effects of these inhibitors dissipated in a time-dependent manner after washout, with more than 75% of ChE activity restored by 4 h after washout. The k values of ChE inhibitors approached 0.50 h −1 , except for distigmine, where k could not be determined. Compared with that of other ChE inhibitors, the potentiating effect of distigmine on UB contractile function was significantly more sustainable following washout, which was likely associated with its corresponding long-lasting ChE inhibitory effect. Distigmine may associate more strongly with UB ChE than other ChE inhibitors, which would partly explain its sustained effects.

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Approaches to the Rational Design of Enzyme Inhibitors

McLeish

Kenyon

2003

Burger's Medicinal Chemistry and Drug Discovery

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Selective inhibitors of enzyme‐catalyzed reactions are widely used in both biochemical and medical science. The inhibitor may be used to block either a single enzyme or a metabolic pathway. The utility of an enzyme inhibitor as a mechanistic probe or a therapeutic agent will depend, in part, on the potency of the inhibitor and its specificity toward its target enzyme. These properties will, in turn, depend on the number and type of interactions the inhibitor makes with the enzyme and the overall mode of inhibition. Here we provide a concise overview of the forces involved in inhibitor binding, and a brief summary of the treatment of enzyme kinetic data. Enzyme inhibitors have been divided into two groups, reversible and irreversible, based on whether the inhibitor binds covalently to its target enzyme. Within these groups inhibitors have been classified on the basis of kinetics, structure, and mechanism. Examples are provided in all cases and, where possible, these are of inhibitors possessing therapeutic interest. The criteria for inclusion in each class of inhibitor are described, as well as the kinetic implications, with particular reference to the specificity of the inhibition. Treatment of the examples includes discussion of the design aspects and, if appropriate, a historical perspective that demonstrates the development of a rational approach to inhibitor design.

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Long chain analogs of physostigmine as potential drugs for Alzheimer's disease: new insights into the mechanism of action in the inhibition of acetylcholinesterase

Cited by 60 publications

References 13 publications

Long-Lasting Inhibitory Effects of Distigmine on Recombinant Human Acetylcholinesterase Activity

Long-Lasting Inhibitory Effects of Distigmine on Recombinant Human Acetylcholinesterase Activity

The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity

Approaches to the Rational Design of Enzyme Inhibitors

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