DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

912 antagonists has yet emerged as a therapeutic agent (Sander et al.,
2008). The H 4
receptor is most similar to the H 3
receptor but is
expressed in cells of hematopoietic lineage; the availability of H 4
-
specific antagonists with anti-inflammatory properties should help to
define the biological roles of the H 4
receptor (Thurmond et al., 2008).
Chemistry. Histamine is a hydrophilic molecule consisting of an
imidazole ring and an amino group connected by two methylene
groups. The pharmacologically active form is the monocationic
Nγ–H tautomer, which is the charged form of the species depicted in
Figure 32–1 (Ganellin and Parsons, 1982). H 3
and H 4
receptors have
a much higher affinity for histamine than H 1
and H 2
receptors, and
the four histamine receptors can be activated differently by analogs
of histamine (Venable and Thurmond, 2006) (Figure 32–1 and
Table 32–1). The specificities of histamine analogs were re-evaluated
after the discovery of the H 4
receptor. Thus, 4-methylhistamine
and dimaprit, originally classified as H 2
receptors (Black et al.,
1972), are full H 4
agonists with a ~100-fold higher affinity for the
H 4
receptor. A number of H 3
agonists also are weaker agonists of
the H 4
receptor (Lim et al., 2005; Venable and Thurmond, 2006).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Distribution and Biosynthesis of Histamine
Distribution. Histamine is widely, if unevenly, distributed
throughout the animal kingdom and is present
in many venoms, bacteria, and plants. Almost all
H 1 RECEPTOR AGONISTS
HN
N
HISTAMINE
H 2 RECEPTOR AGONISTS
mammalian tissues contain histamine in amounts
ranging from <1 to >100 μg/g. Concentrations in
plasma and other body fluids generally are very low,
but human cerebrospinal fluid (CSF) contains significant
amounts. The mast cell is the predominant storage
site for histamine in most tissues; the concentration
of histamine is particularly high in tissues that contain
large numbers of mast cells, such as skin,
bronchial mucosa, and intestinal mucosa.
Synthesis, Storage, and Metabolism. Histamine is
formed by the decarboxylation of the amino acid histidine
by the enzyme L-histidine decarboxylase (Figure
32-2), found in every mammalian tissue that contains
histamine. The chief site of histamine storage in most
tissues is the mast cell; in the blood, it is the basophil.
These cells synthesize histamine and store it in secretory
granules.
At the secretory granule pH of ~5.5, histamine is positively
charged and ionically complexed with negatively charged acidic
groups on other granule constituents, primarily proteases and
heparin or chondroitin sulfate proteoglycans. The turnover rate of
CH 2 CH 2 NH 2
H 3 + H 4 RECEPTOR AGONISTS
CH 2 CH 2 NH 2
HN N
CH 3
2-METHLYHISTAMINE
H 2 N
N NH 2
C
C SCH 2 CH 2 CH 2 N(CH 3 ) 2
N N NH
HN
3 H
DIMAPRIT
(R)-α-METHLYHISTAMINE
CH 2 CH 2 NH 2 N
H 3 C CH2 CH 2 NH 2
N
H 2 N
S NH 2 HN N
2-PYRIDYLETHYLAMINE
AMTHAMINE
4-METHLYHISTAMINE
H 3 C CH 2 SCH 2 CH 2 HNCNHCH 2 CH 2 CH 2 S NH 2
S
NH
N
HN N
N NH HN N NH
2-THIAZOLYLETHYLAMINE
IMPROMIDINE
IMETIT
Figure 32–1. Structure of histamine and some H 1
, H 2
, H 3
, and H 4
agonists- Dimaprit and 4-methylhistamine, originally identified as
specific H 2
agonists, have a much higher affinity for the H 4
receptor; 4-methylhistamine is the most specific available H 4
agonist, with
~10-fold higher affinity than dimaprit, a partial H 4
agonist. Impromidine is among the most potent H 2
agonists but also is an antagonist
at H 1
and H 3
receptors and a partial agonist at H 4
receptors. (R)-α-Methylhistamine and imetit are high-affinity agonists of H 3
receptors and lower-affinity full agonists at H 4
receptors.