Biomedical Engineering Reference
In-Depth Information
NH
2
HN
N
NH
2
NH
2
NH
2
S
HN
N
N
N
Br
Histamine
(endogenous ligand)
2-(3-Bromophenyl)
histamine
2-Pyridylethylamine
2-Thiazolylethylamine
N
N
N
NO
HN
HN
CH
3
N
N
N
HN
CH
3
N
H
NH
Methylhistaprodifen
Suprahistaprodifen
Lisuride
FIGURE 17.1
Histamine H
1
receptor agonists.
imidazole ring is not obligatory, as rel ected by the selective H
1
agonists 2-pyridylethylamine and
2-thiazolylethylamine. Substitution of the imidazole ring at the 2-position will lead to relatively
selective H
1
agonists. For example, 2-(3-bromophenyl)histamine is a relatively potent H
1
recep-
tor agonist. Schunack and colleagues subsequently developed a series of so-called histaprodifens
on the basis of the hypothesis that the introduction of a diphenylalkyl substituent on the 2-position of
the imidazole ring yields high afi nity agonists. This hypothesis was based on the realization that
a diphenylmethyl group is a common feature of high-afi nity H
1
antagonists (see Section 17.2.3).
The introduction of the diphenylpropyl substituent at the 2-position of the imidazole ring and
N-methylation of the ethylamine side chain results in the high potency agonist
N
-methyl-
histaprodifen. Further modii cations of the diphenylmethyl moiety were unsuccessful and
indicated a considerable difference in structure-activity relationship (SAR) (and most likely
receptor-binding site) of the diphenyl moieties of the histaprodifens and the structurally related
H
1
antagonists. A further increase in H
1
receptor agonist potency was obtained by a bivalent
ligand approach. Suprahistaprodifen, a dimer of histaprodifen and histamine is currently one
of the most potent H
1
receptor agonists available. Surprisingly, recent high-throughput screening
(HTS) of CNS-active drugs at the histamine H
1
receptor has identii ed the nonimidazole ergot
derivative lisuride as another high afi nity H
1
receptor agonist.
17.2.3 H
1
R
ECEPTOR
A
NTAGONISTS
The i rst antihistamines were identii ed and optimized by exclusively studying
in vivo
activities.
This might be the explanation why several compounds originally reported as antihistamines were
later on developed for other applications; e.g., the i rst so-called tricyclic antidepressants (e.g., doxepin)
are often also very potent H
1
antagonists. More modern approaches, using genetically modii ed cells
expressing the human H
1
receptor, currently provide more in-depth information on the molecular
mechanism of actions. All therapeutically used H
1
antagonists, in fact, act as inverse agonists (see
Chapter 12) and favor an inactive conformation of the GPCR protein. In view of the detectable level
