absorbed orally. The addition of a 4-methyl group further improved binding to the H 2
receptor. Introduction of the electron-withdrawing sulfur atom into the side chain
reduced the ring pKa. The proportion of the cationic form was also decreased, and the
tele tautomer became predominant. Reduced ionization improved the membrane per-
meability of the molecule; the oral absorption of the resulting compound, metiamide
(4.152), was excellent, and the compound had an activity 10 times higher than that of
burimamide. However, metiamide still showed some side effects in the form of hema-
tological and kidney damage, which were attributed to the thiourea group.
A satisfactory replacement was found by substituting another electron-withdrawing
group on guanidine while retaining the appropriate pKa. A cyano group proved suitable,
and the safe and effective cimetidine (4.153) resulted, which became a drug of choice
in treating peptic ulcer. It then became clear that an imidazole nucleus was not
absolutely necessary for H 2 -antagonist activity. The furan derivative ranitidine (4.154)
is even more active than cimetidine, and famotidine (4.155) is seven times more active
still. Since none of these compounds is lipid soluble (their average partition coefficient
is only 2, compared with coefficients of up to 1000 for typical H 1 antagonists), they do
not produce any sedative CNS action since they cannot cross the blood–brain barrier.
H 2 Antagonists and the Treatment of Peptic Ulcers. Treatment of peptic ulcers is a
complicated and multilevel therapy in which H 2 antagonists are very successful and
widely used (and abused). Peptic ulcers may affect either the stomach (gastric ulcers,
less common overall but more common in people with iatrogenic [i.e., physician-
induced] ulcers from the use of nonsteroidal anti-inflammatory drugs [NSAIDs]) or
the duodenum (duodenal ulcers). The lining of the stomach or duodenum is attacked by
the digestive juices to such an extent that the protective mucous layer on the surface has
NEUROTRANSMITTERS AND THEIR RECEPTORS 267