Biomedical Engineering Reference
In-Depth Information
N
N
N
NH
2
NH
2
N
N
N
CH
3
NH
S
HN
HN
HN
N
α
-Guanylhistamine
(pA
2
= 3.88)
Histamine
Burimamide
(pA
2
= 5.1)
NH
2
N
N
N
N
N
N
N
S
CH
3
S
CH
3
S
N
SO
2
NH
2
N
H
2
N
N
S
S
HN
HN
CN
CH
3
CH
3
NH
2
Cimetidine
(pA
2
= 6.1)
Metiamide
(pA
2
= 6.0)
Famotidine
(pA
2
= 7.8)
N
N
N
O
S
S
CH
3
N
O
N
N
NO
2
CH
3
N
H
3
C
Ranitidine
(pA
2
= 7.2)
Zolantidine
(pA
2
= 7.2)
SCHEME 17.2
Stepwise structural modii cations leading to the development of histamine H
2
receptor drugs
to treat gastric ulcers.
The brain-penetrating H
2
antagonist zolantidine represents a rather nonclassical structure with
the oxygen atom of the furan ring in ranitidine placed outside the aromatic ring and replacement of
the polar group with a benzothiazole group (Scheme 17.2) and has become an important tool for
in vivo
CNS studies.
Like the H
1
receptor, the H
2
receptor was reported to be spontaneously active in transfected
CHO cells. Based on this concept, many H
2
antagonists were reclassii ed: cimetidine, ranitidine,
and famotidine are in fact inverse agonists, whereas burimamide acts in this model system as
a neutral antagonist. This difference in pharmacological proi le was also seen in a differential
effect on H
2
receptor regulation; whereas long-term treatment with inverse agonists, like cime-
tidine, resulted in H
2
receptor upregulation, exposure to the neutral antagonist burimamide did
not affect the receptor expression. Such receptor upregulation was also observed in rabbit pari-
etal cells, resulting in acid hypersecretion after H
2
antagonist withdrawal. These data present
a mechanistic explanation for the known tolerance induction by H
2
antagonist that sometimes
occurs in man.
17.3.4 T
HERAPEUTIC
U
SE
OF
H
2
R
ECEPTOR
L
IGANDS
At the moment there is no clinical application of H
2
agonists, although sometimes histamine is used
as a diagnostic aid in patients with stomach problems. In contrast, H
2
antagonists have proven to
be very effective drugs to alleviate the symptoms of duodenal ulcers, stomach ulcers, and rel ux
oesophagitits. Nowadays, the blockbuster status of the H
2
antagonists has been strongly reduced
with the introduction of the proton pump inhibitors, like omeprazole, to directly inhibit the gastric
acid secretion and the eradication of
Helicobacter pylori
with antibiotics as actual cure, instead of
symptomatic treatment.
