Biomedical Engineering Reference
In-Depth Information
O
H
N
N
N
N
O
O
N
N
N
N
Cl
Diphenhydramine
Mepyramine
Triprolidine
Cetirizine
N
N
N
OH
N
N
OH
N
O
Cl
COOH
F
Astemizole
Fexofenadine
Desloratidine
COOH
N
N
O
O
Doxepin
HY-2901
FIGURE 17.2
Histamine H
1
receptor antagonists (inverse agonists).
of spontaneous activity of the H
1
receptor (i.e., receptor signaling without agonist, also known as
constitutive GPCR activity), all the H
1
antagonists tested so far inhibit the constitutive activation of
e.g., nuclear factor-
B).
Of the many i rst generation histamine blockers, diphenhydramine (Figure 17.2) is considered
as the archetype. The compound is known in medicine as Benadryl
®
, the i rst antihistamine suc-
cessfully used in man. Other compounds of this class are, e.g., mepyramine and triprolidine. These
compounds are highly potent H
1
antagonists and very useful both for pharmacological investiga-
tions and medicinal use. The so-called classical “antihistamines” easily penetrate the brain and are
therefore also useful for
in vivo
CNS studies.
The early antihistamines had two major drawbacks: they were ligands for several targets; espe-
cially the antimuscarinic effects caused unpleasant side effects (e.g., dry mouth). By careful struc-
tural modii cations, it is possible to obtain selective antihistamines. Another drawback of the i rst
generation H
1
antagonists was that the compounds show strong sedating effects, to such a level that
some of them are still used as sleeping aids.
The notion that sedation is caused by a blockade of H
1
receptors in the brain, sparked the search
for nonbrain penetrating compounds. Minor structural modii cations resulted in a number of new,
nonsedating H
1
antagonists (e.g., cetirizine, astemizole, fexofenadine, and desloratidine), also referred
to as the second-generation H
1
blockers. Interestingly, the i rst of such compounds were more or
less found by chance and it took quite some time to understand why the compounds did not manifest
CNS effects. It is now understood that these compounds act as substrates of the P-glycoprotein (PgP)
transport system in the blood-brain barrier. Consequently, these compounds are actively transported
κ
B (NF-
κ
