Biomedical Engineering Reference
In-Depth Information
out of the brain and thereby are not able to occupy signii cant amounts of brain H
1
receptors. The
new class of compounds, including terfenadine (later on due to HERG-blockade replaced by its active
metabolite fexofenadine), cetirizine (now replaced by the l-enantiomer), and loratidine (now replaced
by its desoxy-active metabolite, desloratidine) reached as antiallergics the blockbuster status.
Although effective in treating allergic reactions, the second-generation H
1
antagonists do not
display signii cant antiinl ammatory effects. Currently, research focuses on compounds also target-
ing inl ammation; compounds having besides H
1
blocking properties antagonizing also, e.g., LTB
4
or blocking the synthesis of leukotrienes, have the interest of pharmaceutical companies. Recently,
the combined blockade of H
1
and H
4
receptors (see below) has also been indicated as an attractive
new approach. Interestingly, since the turn of the century the interest in the sleep promoting effects
of histamine H
1
receptor antagonists has increased. Especially, the “old” derivative doxepin, a com-
pound that blocks the H
1
receptor and also the H
2
receptor is used as a sleep inducer. An analog of
doxepin, HY-2901, has been shown to have interesting properties for use as a sleep inducer and is
currently under clinical evaluation as sleep aid.
17.2.4 T
HERAPEUTIC
U
SE
OF
H
1
R
ECEPTOR
L
IGANDS
The histamine H
1
receptor is a well-established drug target and has been thoroughly studied for
decades. The i rst- but especially the second-generation antihistamines are clinically very success-
ful and are widely available drugs. The main indications are hay fever, allergic rhinitis, and con-
junctivitis as well as comparable allergic affections; the application for asthmatic conditions does
not seem to be of much use. The i rst generation antihistamines are still used as in over the counter
(OTC) sleep aids or antil u combination pills. As indicated before, currently interest in sleep aids is
increasing and new molecules are being developed (e.g., HY-2901).
17.3 THE HISTAMINE H
2
RECEPTOR: MOLECULAR
ASPECTS AND SELECTIVE LIGANDS
17.3.1 M
OLECULAR
A
SPECTS
OF
THE
H
ISTAMINE
H
2
R
ECEPTOR
P
ROTEIN
The fact that the “antihistamines” did not antagonize histamine-induced effects at the stomach and
the heart, led in 1966 to the proposal by Ash and Schild of two distinct histamine receptors: the H
1
and H
2
receptors. This hypothesis became generally accepted in 1972 when Black and his cowork-
ers at Smith, Kline & Beecham presented burimamide and related compounds. These ligands
antagonize the effects of histamine on the stomach and the heart. Nowadays, the H
2
receptor is (as
all histamine receptor subtypes) known to belong to the rhodopsin-like family of GPCRs. Using a
polymerase chain reaction (PCR)-based method, based on the known sequence similarity of various
GPCRs and gastric parietal mRNA, the H
2
receptor nucleotide sequence was elucidated. This DNA
sequence encodes for a 359 amino acid GPCR receptor protein. Soon thereafter, the intronless genes
encoding the rat, human, guinea pig, and mouse H
2
receptor were cloned by means of homology.
The H
2
receptor proteins are slightly different in length, highly homologous, and do not show major
pharmacological differences. Interestingly, several polymorphisms have been found in the human
H
2
receptor gene and one of the mutations might be linked to schizophrenia.
The histamine H
2
receptor is positively coupled to the adenylate cyclase system via G
s
prot ei ns i n a
variety of tissues (e.g., brain, stomach, heart, gastric mucosa, and lungs). Moreover, cell lines recom-
binantly expressing the H
2
receptor show increases in cAMP following H
2
receptor activation.
17.3.2 H
2
R
ECEPTOR
A
GONISTS
A simple modii cation of the histamine molecule has not been very successful to obtain selective
and potent H
2
receptor agonists. A i rst step toward an H
2
receptor agonist was made with the