170 Heterocycles in Medicine
For convenience, the following sections on receptor-based drugs are grouped, where possible, according to the natural
neurotransmitter or enzyme to which the drugs relate and may include central and peripheral actions. A separate sec-
tion on CNS-specifi c drugs with more complex mechanisms is included later. Subsequent major sections (infection
and cancer) are, of necessity, related to disease areas.
Histamine
There are two main histamine receptors and action at the H 1 receptor is mainly known for producing allergic responses,
for example hay fever and skin reactions such as urticaria (‘nettle rash’). Antagonists at this receptor, which suppress
these actions of histamine, are well known to the layman, under the loose description ‘antihistamines’ , as hay fever
remedies. The allergic response is quite complex and other mediators, such as leukotrienes, may also be released, hence
the use of leukotriene antagonists, such as montelucast (page 168), for the treatment of asthma and allergies.
Typical H 1 antagonists are not particularly structurally reminiscent of histamine. Early compounds often had side-
effects caused by actions at other receptors, such as that for acetylcholine, but their main drawback is antagonism of
H 1 receptors in the CNS, leading to drowsiness. Promethazine has such strong effects in the CNS that it has found use
as a sedative and is also of use for treatment of motion sickness. Others, such as chlorpheniramine, show only moder-
ate sedative effects. More recently, compounds such as loratidine have been devised that do not enter the CNS and are
therefore free from sedative effects.
The H 2 receptor is part of a complex system involved in mediating release of acid into the stomach. Although this is an
essential part of digestion, excessive amounts of acid can lead to simple indigestion or acid refl ux (heartburn) but can
also cause or aggravate the more serious medical problem of peptic ulcers. The development, in the 1970s, of selective
H 2 antagonists that inhibit the release of gastric acid was a major advance in medicine, as they are very effective in treat-
ing ulcers and have almost eliminated the need for surgery. They were an enormous fi nancial success because of this.
The fi rst compound developed was cimetidine, which is obviously closely structurally related to histamine and, as such,
a more ‘logically’ designed compound than the H 1 antagonists. Other H 2 antagonists, particularly ranitidine followed,
which had an even more favourable side-effect profi le. The dimethylaminomethyl-furan unit in ranitidine can be visual-
ised as replacing the imidazole ring at the receptor. A closer imidazole-substitute is the thiazole ring found in famotidine.
Another type of antacid is the proton pump inhibitor. As mentioned above, H 2 receptors initiate a complex cascade result-
ing in the production of gastric acid, but the actual fi nal release of the acid from the cell is via an enzyme – H,K-ATPase,
the ‘proton pump’ – which exchanges protons from inside the cell with potassium ions from outside. Omeprazole was
designed to deactivate this enzyme and is even more effective than the H 2 antagonists, almost completely stopping the
production of acid. The mechanism of action of omeprazole is very different from competitive H 2 antagonism, it being a
highly selective sulfenylating agent for the SH of a specifi c cysteine residue in the enzyme. This disulfi de formation irre-
versibly deactivates the enzyme so effectively that recovery of acid production requires the biosynthesis of new enzyme.