DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

A. Association of ACh
Tetrahedral transition state Acetyl enzyme Hydrolysis of acetyl enzyme
241
Glu 334
Ser 203
His 447
Glu 334
Ser 203
His 447
Glu 334
Ser 203
His 447
Glu 334
Ser 203
His 447
Gly 122
Gly 121
choline
B. Edrophonium complex C. Reversible neostigmine binding Dimethyl carbamoyl enzyme Hydrolysis of dimethyl
Glu 334
carbamoyl AChE
Glu 334
Ser 203
His 447
D. Reversible DFP binding
Glu 334
His 447
Ser 203
Glu 334
Ser 203
His 447
Diisopropyl phosphoryl AChE
Glu 334 Glu 334
Ser 203 Ser 203
His 447 His 447
His 447
Ser 203
Aged monoisopropyl
phosphoryl AChE
carbon oxygen nitrogen hydrogen phosphorus fluorine
Glu 334
Glu 334
His 447
His 447
Ser 203
Ser 203
E. Reactivation of
DFP-AChE by 2-PAM
Gly 122 Gly 122 Gly 122
Gly 121 Gly 121
Gly 121
2PAM
Figure 10–2. Steps involved in the hydrolysis of acetylcholine by acetylcholinesterase and in the inhibition and reactivation of the
enzyme. Only the three residues of the catalytic triad shown in Figure 10–1 are depicted. The associations and reactions shown are:
A. Acetylcholine (ACh) catalysis: binding of ACh, formation of a tetrahedral transition state, formation of the acetyl enzyme with liberation
of choline, rapid hydrolysis of the acetyl enzyme with return to the original state. B. Reversible binding and inhibition by edrophonium.
C. Neostigmine reaction with and inhibition of AChE: reversible binding of neostigmine, formation of the dimethyl
carbamoyl enzyme, slow hydrolysis of the dimethyl carbamoyl enzyme. D. Diisopropyl fluorophosphate (DFP) reaction and inhibition
of AChE: reversible binding of DFP, formation of the diisopropyl phosphoryl enzyme, formation of the aged monoisopropyl
phosphoryl enzyme. Hydrolysis of the diisopropyl enzyme is very slow and is not shown. The aged monoisopropyl phosphoryl enzyme
is virtually resistant to hydrolysis and reactivation. The tetrahedral transition state of ACh hydrolysis resembles the conjugates formed
by the tetrahedral phosphate inhibitors and accounts for their potency. Amide bond hydrogens from Gly121 and Gly122 stabilize the
carbonyl and phorphoryl oxygens. E. Reactivation of the diisopropyl phosphoryl enzyme by pralidoxime (2-PAM). 2-PAM attack of
the phosphorus on the phosphorylated enzyme will form a phospho- oxime with regeneration of active enzyme. The individual steps
of phosphorylation reaction and oxime reaction have been characterized by mass spectrometry (Jennings et al., 2003).
CHAPTER 10
ANTICHOLINESTERASE AGENTS
very labile to hydrolysis, which results in the formation of acetate
and active enzyme (Froede and Wilson, 1971; Rosenberry, 1975).
AChE is one of the most efficient enzymes known: one molecule of
AChE can hydrolyze 6 × 10 5 ACh molecules per minute; this yields
a turnover time of 100 microseconds.
Mechanism of Action of AChE Inhibitors. The mechanisms
of the action of compounds that typify the
three classes of anti- ChE agents are also shown in
Figure 10–2.
Three distinct domains on AChE constitute binding sites for
inhibitory ligands and form the basis for specificity differences
between AChE and butyrylcholinesterase: the acyl pocket of the active
center, the choline subsite of the active center, and the peripheral
anionic site (Reiner and Radic´, 2000; Taylor and Radic´, 1994).
Reversible inhibitors, such as edrophonium and tacrine, bind to the
choline subsite in the vicinity of Trp86 and Glu202 (Silman and
Sussman, 2000) (Figure 10–2B). Edrophonium has a brief duration
of action because its quaternary structure facilitates renal elimination
and it binds reversibly to the AChE active center. Additional
reversible inhibitors, such as donepezil, bind with higher affinity to
the active center.
Other reversible inhibitors, such as propidium and the snake
peptidic toxin fasciculin, bind to the peripheral anionic site on AChE.
This site resides at the rim of the gorge and is defined by Try286 and
Tyr72 and Tyr124 (Figure 10–1).
Drugs that have a carbamoyl ester linkage, such as physostigmine
and neostigmine, are hydrolyzed by AChE, but much more
slowly than is ACh. The quaternary amine neostigmine and the