well as of donating and accepting hydrogen. It produces a higher maximum gastric acid
secretion in dogs than does histamine.
The pharmacological effects of histamine may be summarized as follows:
- The circulatory effects are manifested as arteriolar dilation and increased capillary
permeability, causing plasma loss. The localized redness, edema (hives, wheal), and
diffuse redness seen in allergic urticaria (rash) or physical skin injury result from
these circulatory changes. Vasodilation also causes a decrease in blood pressure. - The effects on the heart (H 2 response) are minor, but the heart rate increases.
- Humans and guinea pigs are very prone to bronchoconstriction by histamine (an H 1
effect), and severe asthmatic attacks can be triggered by small doses, provided the
person suffers from asthma and is therefore very sensitive to histamine. - Stimulation of gastric acid secretion is the most important H 2 response; it is blocked
only by H 2 antagonists. As mentioned before, the hormone gastrin may be involved
in histamine release, because H 2 antagonists block gastrin-induced acid secretion. - H 3 receptors are involved in mediating the neuroregulatory influence of the brain on
stomach, lung, and heart. Structural alterations of histamine result in (R)-α-methyl-
histamine (4.145), a potent and selective H 3 agonist. Replacement of the amino
group with bioisosteric polar cationic groups yields imetit (4.146) and immepip
(4.147), other potent and selective H 3 agonists.
4.6.4 Histamine Antagonists4.6.4.1 H 1 Antagonists
Antagonists of the H 1 receptor were first discovered by Bovet in 1933. They do not bear
any close resemblance to the agonist since their binding involves accessory binding sites.
Ethylenediamines, aminoalkyl ethers, and aminopropyl compounds, for which X is
nitrogen, oxygen, and carbon, respectively, show a general H 1 antagonist structure.
Cyproheptadine (4.122), a serotonin antagonist, is also a potent antihistamine (about
150 times more active than diphenhydramine,2.5), and so is promethazine (3.5) and
its derivatives, which, formally at least, can be considered a result of ring closure
connecting the two aryl rings in a diphenyl-ethylenediamine.
The unpleasant sedative CNS effect of most antihistamines, combined with their
slight anticholinergic activity, is exploited for the prevention of motion sickness.
Diphenhydramine (2.5), in the form of an 8-chlorotheophylline salt (dimenhydrinate,
4.148), is widely used for this purpose. The theophylline derivative was originally
added to counteract the drowsiness produced by diphenhydramine, since it is a central
excitant related to caffeine.
NEUROTRANSMITTERS AND THEIR RECEPTORS 265