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

350 mCPP, an active metabolite of the antidepressant drug trazodone,
has been employed to probe brain 5-HT function in humans,
where it alters a number of neuroendocrine parameters and elicits
profound behavioral effects, with anxiety as a prominent symptom.
Animal studies suggest a greater involvement of the 5-HT 2C
receptor
in the anxiogenic actions of mCPP. mCPP elevates cortisol and
prolactin secretion, probably through a combination of 5-HT 1
and
5-HT 2A/2C
receptor activation. It also increases growth hormone
secretion, apparently by a 5-HT independent mechanism.
SECTION II
NEUROPHARMACOLOGY
5-HT Receptor Antagonists
The properties of 5-HT receptor antagonists also vary
widely. Ergot alkaloids and related compounds tend to be
nonspecific 5-HT receptor antagonists; however, a few
ergot derivatives, such as metergoline, bind preferentially
to members of the 5-HT 2
receptor family. A number of
selective antagonists for 5-HT 2A/2C
and 5-HT 3
receptors
are currently available. Members of these drug classes
have widely different chemical structures, with no common
structural motif predictably conveying high affinity.
Ketanserin is the prototypic 5-HT 2A
receptor antagonist.
A large series of 5-HT 3
receptor antagonists are being
explored for treatment of various GI disturbances (e.g.,
ondansetron [ZOFRAN, others], dolasetron [ANZEMET],
granisetron [KYTRIL, others], and palonosetron [ALOXI]).
All 5-HT 3
receptor antagonists have proven to be highly
efficacious in the treatment of chemotherapy-induced
nausea, and alosetron (LOTRONEX) is licensed for irritable
bowel syndrome (Chapter 46).
Clinical effects of 5-HT related drugs often
exhibit a significant delay in onset. This is particularly
the case with drugs used to treat affective disorders such
as anxiety and depression (see Chapter 15). This
delayed onset has generated considerable interest in
potential adaptive changes in 5-HT receptor density and
sensitivity after chronic drug treatments.
Laboratory studies have documented agonist-promoted
receptor subsensitivity and down-regulation of 5-HT receptor subtypes,
a compensatory response common to many neurotransmitter
systems. However, an unusual adaptive process, antagonist-induced
down-regulation of 5-HT 2A
/5-HT 2C
receptors, takes place in rats and
mice after chronic treatment with receptor antagonists (Gray and
Roth, 2001). The mechanism of this paradoxical regulation of
5-HT 2A/2C
receptors has generated considerable interest, since many
clinically effective drugs, including clozapine, ketanserin (not
licensed for use in the U.S.), and amitriptyline, exhibit this unusual
property. These drugs, as well as several other 5-HT 2A/2C
-receptor
antagonists, possess negative intrinsic activity, reducing constitutive
(spontaneous) receptor activity as well as blocking agonist occupancy.
This property of negative intrinsic activity or inverse agonism
is frequently observed when constitutive (agonist-independent)
activity can be measured; in the absence of constitutive activity,
inverse agonists behave as competitive antagonists. Another group
of 5-HT 2A/2C
receptor antagonists acts in the classical manner, simply
blocking receptor occupancy by agonists. Recent evidence for constitutive
activity of the 5-HT 2C
receptor in vivo (Aloyo et al., 2009)
justifies refinement of drug development to target pre-existing constitutive
neuronal activity as opposed to blockade of excess neurotransmitter
action.
Ketanserin. Ketanserin (SUFREXAL, others) opened a new
era in 5-HT receptor pharmacology. Ketanserin potently
blocks 5-HT 2A
receptors, less potently blocks 5-HT 2C
receptors, and has no significant effect on 5-HT 3
or 5-HT 4
receptors or any members of the 5-HT 1
-receptor family.
Notably, ketanserin also has high affinity for α adrenergic
receptors and histamine H 1
receptors.
KETANSERIN
Ketanserin lowers blood pressure in patients with
hypertension, causing a reduction comparable to that
seen with β adrenergic-receptor antagonists or diuretics.
The drug appears to reduce the tone of both capacitance
and resistance vessels. This effect likely relates to its
blockade of α 1
adrenergic receptors, not its blockade of
5-HT 2A
receptors. Ketanserin inhibits 5-HT-induced
platelet aggregation, but it does not greatly reduce the
capacity of other agents to cause aggregation. Severe
side effects after treatment with ketanserin have not
been reported. Its oral bioavailability is ~50%, and its
plasma t 1/2
is 12-25 hours. The primary mechanism of
inactivation is hepatic metabolism. Ketanserin is not
marketed in the U.S. but is available in Europe.
Chemical relatives of ketanserin such as ritanserin are more
selective 5-HT 2A
receptor antagonists with low affinity for α 1
adrenergic
receptors. However, ritanserin, as well as most other 5-HT 2A
receptor antagonists, also potently antagonize 5-HT 2C
receptors. The
physiological significance of 5-HT 2C
-receptor blockade is unknown.
M100,907 is the prototype of a new series of potent 5-HT 2A
receptor
antagonists, with high selectivity for 5-HT 2A
versus 5-HT 2C
receptors.
Clinical trials of M100,907 in the treatment of schizophrenia have
been inconclusive.
Atypical Antipsychotic Drugs. Clozapine (CLOZARIL,
others), a 5-HT 2A/2C
receptor antagonist, represents a
class of atypical antipsychotic drugs with reduced incidence
of extrapyramidal side effects compared to the
classical neuroleptics, and possibly a greater efficacy
for reducing negative symptoms of schizophrenia
(Chapter 16). Clozapine also has a high affinity for subtypes
of DA receptors.
A common strategy for the design of additional
atypical antipsychotic drugs is to combine 5-HT 2A/2C
and