Biomedical Engineering Reference
In-Depth Information
subtype regulates the release and synthesis of histamine. In addition, the H
3
receptor regulates
the release of other important neurotransmitters, such as acetylcholine, serotonin, noradrenalin,
and dopamine. Next to its high expression in certain regions of the human brain (for example, the
basal ganglia, hippocampus, and cortical areas, i.e., the parts of the brain that are associated with
cognition) the H
3
receptor is also present to some extent in the peripheral nervous system, e.g., in
the gastrointestinal tract, the airways, and the cardiovascular system.
Initial efforts to identify the H
3
receptor gene, using the anticipated homology with the previ-
ously identii ed H
1
and H
2
receptor genes ended in vain. Eventually, the human H
3
receptor cDNA
was identii ed by Lovenberg and his coworkers at Johnson & Johnson in 1999. In search for novel
GPCR proteins using a homology search of commercial genome databases, a receptor with high
similarity to the M
2
muscarinic acetylcholine receptor and high brain expression was identii ed.
Expression of the gene and full pharmacological characterization established this protein as the
histamine H
3
receptor. Cloning of the H
3
receptor genes of other species, including rat, guinea pig,
and mouse, soon followed, and important H
3
receptor species differences have been identii ed. The
H
3
receptor mRNA undergoes extensive alternative splicing, resulting in many H
3
receptor isoforms
that have different signaling properties and expression proi les. Moreover, the H
3
receptor displays
particularly high constitutive activity, which can also be observed
in vivo
, again leading to a reclas-
sii cation of existing ligands into agonists, neutral antagonists, and inverse agonists.
The H
3
receptor signals via G
i/o
proteins as shown by the pertussis toxin sensitive stimulation of
[
35
S]-GTP
S binding in rat cortical membranes. The inhibition of adenylyl cyclase after stimulation
of the H
3
receptor results in lowering of cellular cAMP levels and modulation of cAMP responsive
element-binding protein (CREB) dependent gene transcription.
γ
17.4.2 H
ISTAMINE
H
3
R
ECEPTOR
A
GONISTS
At the H
3
receptor, histamine itself is an highly active agonist. Methylation of the amino function
results in
N
α
-methylhistamine (Figure 17.4), a compound that is H
3
selective and even more active
than histamine. Methylation of the
-carbon atom of the ethylamine side chain also increases the
potency at the H
3
receptor. This increased activity resides completely in the
R
-isomer; the cor-
responding
S
-isomer is approximately 100-fold less potent. Since the methylation leads to highly
reduced activity at both the H
1
and H
2
receptor, but still substantial activity at the H
4
receptor,
R
-(
α
)-methylhistamine is a moderately selective agonist at the H
3
receptor. In combination with its
less active
S
-isomer, this compound has proven to be highly useful for the pharmacological charac-
terization of H
3
receptor-mediated effects. For potent H
3
agonism, the amine function of histamine
can be replaced by an isothiourea group, as in imetit. This compound is also very active
in vitro
and
in vivo
, as is
R
-(
α
)-methylhistamine. The basic group in the imidazole side chain can also be
incorporated in ring structures. For example, immepip is a potent H
3
agonist that is effective
in vitro
and
in vivo
. Although the described i rst generation H
3
agonists were intensively used as reference
ligands to study the H
3
receptor, all of them proved to have considerable activity for the recently
discovered H
4
receptor. Therefore, a new generation of potent and selective H
3
agonists has been
developed, most notably immethridine (pEC
50
= 9.8; 300-fold selectivity over the H
4
receptor) and
methimepip (pEC
50
= 9.5; >10,000-fold selectivity over the H
4
receptor). These latter compounds are
devoid of high H
4
receptor activity.
α
17.4.3 H
ISTAMINE
H
3
R
ECEPTOR
A
NTAGONISTS
As with the i rst generation H
3
agonists, the i rst generation H
3
antagonists (all of them possessing
an imidazole heterocycle) have considerable afi nity for the more recently discovered histamine H
4
receptor. The i rst potent H
3
receptor antagonist (later reclassii ed as an inverse agonist) that was
devoid of H
1
receptor and H
2
receptor activity was thioperamide (Figure 17.5). This compound
has been used in many H
3
receptor studies as reference ligand and is active
in vitro
and
in vivo
