Biomedical Engineering Reference
In-Depth Information
Especially since the cloning of the H
3
receptor gene in 1999, the pharmaceutical industry has
been actively exploring the potential of H
3
receptor ligands and many new antagonists/inverse
agonists have been described. Typical examples are the inverse agonist ABT-239 and the neutral
antagonist JNJ-5207852 (Figure 17.5). Interestingly, this latter compound is active in several mod-
els for cognition, but does not act as an appetite suppressant and has no effect on food intake.
Other compounds, such as Abbott's A-423579, have good efi cacy in obesity models, but lack clear
procognitive effects. At present the differences in efi cacy for distinct clinical applications of the
different classes of H
3
ligands is not understood (e.g., involvement of different H
3
receptor isoforms)
and subject of intense research.
17.4.4 T
HERAPEUTIC
U
SE
OF
H
ISTAMINE
H
3
R
ECEPTOR
L
IGANDS
Multiple lines of evidence indicate that the H
3
receptor is involved in numerous physiological processes
and that this receptor bears potential as a promising drug target. A handful of applications for H
3
ago-
nists has emerged from preclinical studies in the areas of migraine (modulating release of neurogenic
peptides) and ischemic arrhythmias (modulating noradrenaline release). In migraine, the H
3
agonistic
properties of
N
α
-methylhistamine have been reported to be benei cial in a Phase II trial. Intriguingly,
both H
3
agonists and H
3
inverse agonist are claimed to have a benei cial activity when studied in pre-
clinical obesity models. The full spectrum of diseases, where H
3
receptor mediated treatment might
be applicable, is striking. H
3
antagonists and inverse agonists have been successfully used in animal
models for narcolepsy, cognitive disorders, neuropathic pain, and others. In this respect, GSK-189254
is a remarkable H
3
ligand as it is in trials for three different diseases: neuropathic pain, narcolepsy,
and dementia. It has proven a challenging task to predict in what specii c preclinical model(s) a given
structural series of H
3
antagonist or inverse agonist will be useful. Moreover, a full clinical validation
of the promising role of H
3
receptor antagonists is still awaited.
17. 5 THE HISTAMINE H
4
RECEPTOR: MOLECULAR
ASPECTS AND SELECTIVE LIGANDS
17.5.1 M
OLECULAR
A
SPECTS
OF
THE
H
ISTAMINE
H
4
R
ECEPTOR
P
ROTEIN
Immediately following the cloning of the H
3
receptor gene, several groups identii ed the homologous
H
4
receptor sequence in the human genome databases. Indeed, the H
4
receptor has high sequence
identity with the H
3
receptor (31% at the protein level, 54% in the transmembrane domains). The H
3
and H
4
receptors are also similar in gene structure. The human H
4
receptor gene is present on chro-
mosome 18q11.2 and the gene contains three exons that are interrupted by two large introns (like the
H
3
receptor gene). To date, two H
4
receptor isoforms have been identii ed, but no functional role has
been reported so far. Cloning of the genes that encode the mouse, rat, guinea pig, and pig H
4
recep-
tors reveal only limited sequence homology with the human H
4
receptor. The H
4
receptor is mainly
expressed in bone marrow and peripheral leukocytes and mRNA of the human H
4
receptor is detected
in, e.g., mast cells, dentritic cells, spleen, and eosinophils. The H
4
receptor has a pronounced effect on
the chemotaxis of several cell types that are associated with immune and inl ammatory responses.
The H
4
receptor couples to G
i/o
proteins, thereby leading to a decrease in cAMP production and the
regulation of CREB gene transcription. Furthermore, H
4
receptor stimulation affects the G
i/o
protein
mediated activation of mitogen-activitated protein (MAP) kinase. Studying the increased [
35
S]GTP
γ
S
levels in H
4
transfected cells, it has been shown that also the H
4
receptor is constitutively active.
17.5.2 H
ISTAMINE
H
4
R
ECEPTOR
A
GONISTS
Most of the i rst generation imidazole-containing H
3
ligands have reasonable afi nity for the H
4
recep-
tor as well. The i rst imidazole-containing ligand that was reported to have some selectivity for the
