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

242 tertiary amine physostigmine exist as cations at physiological pH.
CHEMISTRY AND STRUCTURE-ACTIVITY
RELATIONSHIPS
SECTION II
NEUROPHARMACOLOGY
By serving as alternate substrates to ACh (Figure 10–2C), attack by
the active center serine generates the carbamoylated enzyme. The
carbamoyl moiety resides in the acyl pocket outlined by Phe295 and
Phe297. In contrast to the acetyl enzyme, methylcarbamoyl AChE
and dimethylcarbamoyl AChE are far more stable (the t 1/2
for hydrolysis
of the dimethylcarbamoyl enzyme is 15-30 minutes).
Sequestration of the enzyme in its carbamoylated form thus precludes
the enzyme- catalyzed hydrolysis of ACh for extended periods
of time. When administered systemically, the duration of inhibition
by the carbamoylating agents is 3-4 hours.
The organophosphate inhibitors, such as diisopropyl fluorophosphate
(DFP), serve as true hemisubstrates, since the resultant
conjugate with the active center serine phosphorylated or phosphonylated
is extremely stable (Figure 10–2D). The organophosphorus
inhibitors are tetrahedral in configuration, a configuration that resembles
the transition state formed in carboxyl ester hydrolysis. Similar
to the carboxyl esters, the phosphoryl oxygen binds within the
oxyanion hole of the active center. If the alkyl groups in the phosphorylated
enzyme are ethyl or methyl, spontaneous regeneration of
active enzyme requires several hours. Secondary (as in DFP) or tertiary
alkyl groups further enhance the stability of the phosphorylated
enzyme, and significant regeneration of active enzyme usually is not
observed. The stability of the phosphorylated enzyme is enhanced
through “aging,” which results from the loss of one of the alkyl
groups. Hence, the return of AChE activity depends on synthesis of
a new enzyme.
Thus, the terms reversible and irreversible as applied to the
carbamoyl ester and organophosphate anti- ChE agents, respectively,
reflect only quantitative differences in rates of decarbamoylation or
dephosphorylation of the conjugated enzyme. Both chemical classes
react covalently with the active center serine in essentially the same
manner as does ACh.
Action at Effector Organs. The characteristic pharmacological
effects of the anti- ChE agents are due primarily
to the prevention of hydrolysis of ACh by AChE at sites
of cholinergic transmission. Transmitter thus accumulates,
enhancing the response to ACh that is liberated
by cholinergic impulses or that is spontaneously
released from the nerve ending. Virtually all acute
effects of moderate doses of organophosphates are
attributable to this action. For example, characteristic
miosis that follows local application of DFP to the eye
is not observed after chronic postganglionic denervation
of the eye because there is no source from which to
release endogenous ACh. The consequences of
enhanced concentrations of ACh at motor end- plates
are unique to these sites and are discussed later.
The tertiary amine and particularly the quaternary ammonium
anti- ChE compounds may have additional direct actions at
certain cholinergic receptor sites. For example, the effects of
neostigmine on the spinal cord and neuromuscular junction are
based on a combination of its anti- ChE activity and direct cholinergic
stimulation.
The structure- activity relationships of anti- ChE agents
are reviewed in previous editions of this book. Only
agents of general therapeutic or toxicological interest
are considered here.
Noncovalent Inhibitors. While these agents interact by reversible and
noncovalent association with the active site in AChE, they differ in
their disposition in the body and their affinity for the enzyme.
Edrophonium, a quaternary drug whose activity is limited to peripheral
nervous system synapses, has a moderate affinity for AChE. Its
volume of distribution is limited and renal elimination is rapid,
accounting for its short duration of action. By contrast, tacrine and
donepezil (Figure 10–3) have higher affinities for AChE, are more
hydrophobic, and readily cross the blood- brain barrier to inhibit
AChE in the CNS. Their partitioning into lipid and their higher
affinities for AChE account for their longer durations of action.
“Reversible” Carbamate Inhibitors. Drugs of this class that are of
therapeutic interest are shown in Figure 10–3. Early studies showed
that the essential moiety of the physostigmine molecule was the
methylcarbmate of an amine- substituted phenol. The quaternary
ammonium derivative neostigmine is a compound of equal or greater
potency. Pyridostigmine is a close congener that also is used to treat
myasthenia gravis.
An increase in anti- ChE potency and duration of action can
result from the linking of two quaternary ammonium moieties. One
such example is the miotic agent demecarium, which consists of two
neostigmine molecules connected by a series of ten methylene
groups. The second quaternary group confers additional stability to
the interaction by associating with a negatively charged amino side
chain, Asn74, near the rim of the gorge. Carbamoylating inhibitors
with high lipid solubilities (e.g., rivastigmine), which readily cross
the blood- brain barrier and have longer durations of action, are
approved or in clinical trial for the treatment of Alzheimer’s disease
(Cummings, 2004; Giacobini, 2000) (Chapter 22).
The carbamate insecticides carbaryl (SEVIN), propoxur
(BAYGON), and aldicarb (TEMIK), which are used extensively as garden
insecticides, inhibit ChE in a fashion identical with other carbamoylating
inhibitors. The symptoms of poisoning closely
resemble those of the organophosphates (Baron, 1991; Ecobichon,
2000). Carbaryl has a particularly low toxicity from dermal absorption.
It is used topically for control of head lice in some countries.
Not all carbamates in garden formulations are ChE inhibitors; the
dithiocarbamates are fungicidal.
Organophosphorus Compounds. The general formula for this class of
ChE inhibitors is presented in Table 10–1. A great variety of substituents
is possible: R 1
and R 2
may be alkyl, alkoxy, aryloxy, amido,
mercaptan, or other groups; and X, the leaving group, typically a
conjugate base of a weak acid, is a halide, cyanide, thiocyanate, phenoxy,
thiophenoxy, phosphate, thiocholine, or carboxylate group.
For a compilation of the organophosphorus compounds and their
toxicity, see Gallo and Lawryk (1991).
DFP produces virtually irreversible inactivation of AChE and
other esterases by alkylphosphorylation. Its high lipid solubility, low
molecular weight, and volatility facilitate inhalation, transdermal