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

42 signaling compounds are termed agonists. If the drug
binds to the same recognition site as the endogenous
agonist (the primary or orthosteric site on the receptor)
the drug is said to be a primary agonist. Allosteric (allotopic)
agonists bind to a different region on the receptor
referred to as an allosteric or allotopic site. Drugs
that block or reduce the action of an agonist are termed
antagonists. Antagonism most commonly results from
competition with an agonist for the same or overlapping
site on the receptor (a syntopic interaction), but
can also occur by interacting with other sites on the
receptor (allosteric antagonism), by combining with the
agonist (chemical antagonism), or by functional antagonism
by indirectly inhibiting the cellular or physiological
effects of the agonist. Agents that are only partly
as effective as agonists regardless of the concentration
employed are termed partial agonists. Many receptors
exhibit some constitutive activity in the absence of a
regulatory ligand; drugs that stabilize such receptors in
an inactive conformation are termed inverse agonists
(Figure 3–1) (Kenakin, 2004; Milligan, 2003). Note
that partial agonists and inverse agonists that interact
syntopically with a full agonist will behave as competitive
antagonists.
SECTION I
GENERAL PRINCIPLES
Drug Specificity
The strength of the reversible interaction between a
drug and its receptor, as measured by the dissociation
constant, is defined as the affinity of one for the other.
Both the affinity of a drug for its receptor and its intrinsic
activity are determined by its chemical structure.
The chemical structure of a drug also contributes to the
drug’s specificity. A drug that interacts with a single
type of receptor that is expressed on only a limited
number of differentiated cells will exhibit high specificity.
An example of such a drug is ranitidine, an H 2
receptor antagonist used to treat ulcers (Chapter 45). If,
however, a receptor is expressed ubiquitously on a variety
of cells throughout the body, drugs acting on such
a widely expressed receptor will exhibit widespread
effects, and could produce serious side effects or toxicities
if the receptor serves important functions in multiple
tissues.
There are numerous examples of drugs that work
through a discrete action, but have effects throughout
the body. These include the inotropic drug digoxin,
which inhibits the ubiquitously expressed enzyme
Na + ,K + -ATPase (Chapter 28), and the antifolate anticancer
drugs such as methotrexate that inhibit dihydrofolate
reductase, an enzyme required by all cells for the
synthesis of purines and thymidylate (Chapters 60
Level of Response (arbitrary units)
Full agonist
Partial agonist
200 R i LR a
150
100
50
0
Inactive compound
Inverse agonist
Log [Drug]
and 61). The Na + channel blocker lidocaine has effects
in peripheral nerves, the heart, and the central nervous
system (CNS) because Na + channels are highly
expressed in all these tissues (Chapters 20 and 29).
Lidocaine has local anesthetic effects when administered
locally to prevent or relieve pain, but can also have
cardiac and CNS effects if it reaches the systemic circulation.
Even if the primary action of a drug is localized,
as might be the case with injected lidocaine, the
subsequent physiological effects of the drug may be
widespread. One example would be immunosuppressant
drugs (Chapter 35) that specifically inhibit cells of
the immune system; their use is limited by the risk of
LR i
LR i
LR i
L
L
L
LR a
LR a
Figure 3–1. Regulation of the activity of a receptor with
conformation-selective drugs. The ordinate is the activity of the
receptor produced by R a
, the active receptor conformation (e.g.,
stimulation of adenylyl cyclase by a β adrenergic receptor). If a
drug L selectively binds to R a
, it will produce a maximal response.
If L has equal affinity for R i
and R a
, it will not perturb the equilibrium
between them and will have no effect on net activity; L
would appear as an inactive compound. If the drug selectively
binds to R i
, then the net amount of R a
will be diminished. If L can
bind to receptor in an active conformation R a
but also bind to inactive
receptor R i
with lower affinity, the drug will produce a partial
response; L will be a partial agonist. If there is sufficient R a
to
produce an elevated basal response in the absence of ligand
(agonist-independent constitutive activity), then activity will be
inhibited; L will then be an inverse agonist. Inverse agonists selectively
bind to the inactive form of the receptor and shift the conformational
equilibrium toward the inactive state. In systems that
are not constitutively active, inverse agonists will behave like
competitive antagonists, which helps explain why the properties
of inverse agonists and the number of such agents previously
described as competitive antagonists were only recently appreciated.
Receptors that have constitutive activity and are sensitive to
inverse agonists include benzodiazepine, histamine, opioid,
cannabinoid, dopamine, bradykinin, and adenosine receptors.
L
R a