4.6.1 Structure, Conformation, and Equilibria of HistamineProtonation has been an important aspect in the design of some histamine antagonists.
Figure 4.10 shows the tautomeric equilibria between different histamine species and the
respective mole percentages of these species. The most important among them is the
Nt—H (tele-) tautomer, which also appears to be the active form of the agonist on both
receptors. Tautomerism does not appear to be important in H 1 receptor binding (in the intes-
tine); however, it does seem to be important to gastric H 2 –receptor activity. Histamine may
play the role of a proton-transfer agent, in a fashion similar to the charge-relay role of the
imidazole ring in serine esterases. The percentage of the monocation tautomers is greatly
influenced by substituents in position 4, which alter the electron density on the Nπatom,
an important consideration in modifying the receptor-binding properties of histamine.
Histamine metabolism differs from that of classical neurotransmitters because hista-
mine is so widely distributed in the body. The highest concentrations in human tissues
are found in the lung, stomach, and skin (upto 33 μg/g tissue). Histamine metabolic path-
ways are simple; histamine is produced from histidine in just one step (see figure 4.11).
The principal production takes place in the mast cells of the peritoneal cavity and con-
nective tissues. The gastric mucosa is another major storage tissue. Histamine can be
found in the brain as well.
Histamine is released from mast cells in antigen–antibody reactions, as in anaphylaxis
and allergy, which are the most widely known physiological reactions to histamine.
However, these potentially fatal reactions are not caused by histamine alone. Other agents
present in mast cells, such as serotonin, acetylcholine, bradykinin (a nonapeptide), and a
“slow-reacting substance” or leukotriene (see chapter 8) also contribute. In the stomach,
where histamine induces acid secretion, its release seems to be regulated by the peptide
hormone pentagastrin.
4.6.2 Histamine ReceptorsClassically, these receptors have also been divided into three groups. The first of these,
the H 1 receptors, were described by Schild in 1966.The H 2 receptors were discovered
in 1972 by Black et al. The H 3 receptor subtype was described by Arrang in 1983. The
H 1 receptor is found in the smooth muscle of the intestines, bronchi, and blood vessels
and is blocked by the “classical” antihistamines.The H 2 receptor,present in gastric
parietal cells, in guinea pig atria, and in the uterus, does not react to H 1 blockers but
only to specific H 2 antagonists. H 2 receptors also appear to be involved in the
immunoregulatory system and may be present in T lymphocytes, basophil cells, and
mast cells. H 3 receptors are found predominantly in brain but are also localized in
stomach, lung, and cardiac tissue.
H 1 ,H 2 , and H 3 receptors are present in the CNS. Tricyclic antidepressant drugs seem
to interact with histamine receptors in the CNS. Histamine receptor subtypes in the
CNS and the central neurotransmitter role of histamine have been the subject of many
recent investigations. Currently there are three central histamine receptors:
- H 1 receptors are widely distributed, especially in the cerebellum, thalamus, and
hippocampus, and are located on neurons, astrocytes, and blood vessels. H 1 receptors
in brain vary widely from species to species. Since histamine does not easily cross
NEUROTRANSMITTERS AND THEIR RECEPTORS 261