Cimetidine is a non-thiourea analogue of metiamide. It is a specific competitive histamine H2-receptor antagonist and is an effective inhibitor of gastric secretion in animals and man with similar pharmacological properties to metiamide. No renal damage or haematological changes were observed in 90-day studies in rats or dogs.

Histamine exists predominantly as the NT-H tautomer of the monocation (IIa) at a physiological pH of 7.4 and structure-activity studies indicate that this tautomer is likely to be the pharmacologically active species for both H1 and H2 receptors. Effective H2-receptor agonists appear to require a prototropic tautomeric system whereas H1-receptor agonists do not need to be tautomeric. This identifies a chemical difference in the receptor requirements which provides the basis for obtaining selective histamine H1-receptor agonists. Thus 2-(2-aminoethyl)thiazole and 2-(2-aminoethyl)pyridine are nontautomeric and are highly selective agonists for histamine H1 receptors (H1:H2 ca. 90:1 and 30:1, respectively). In conjunction with the selective H2-receptor agonist, 4-methylhistamine, they are of great value for studying the pharmacology of histamine receptors.

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In the histamine H2-receptor antagonist metiamide (2a) isosteric replacement of thione sulfur (=S) by carbonyl oxygen (=O) or imino nitrogen (=NH) affords the urea 2c and guanidine 2d which are antagonists of decreased potency. The guanidine is very basic and at physiological pH is completely protonated. However, introduction of strongly electronegative substituents into the guanidine group reduces basicity and gives potent H2-receptor antagonists, viz. the cyanoguanidine 2b (cimetidine, "Tagamet") and nitroguanidine 2e. A correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4. The close correspondence between cyanoguanidine and thiourea in many physicochemical properties and the pharmacological equivalence of these groups in H2-receptor antagonists leads to the description of cyanoguanidine and thiourea as bioisosteres. Acid hydrolysis of the cyanoguanidine 2b yields the carbamoylguanidine 2f at ambient temperatures and the guanidine 2d at elevated temperatures. Cimetidine is slightly more active than metiamide in vivo as an inhibitor of histamine-stimulated gastric acid secretion and has clinical use in the treatment of peptic ulcer and associated gastrointestinal disorders.

S-[3-(N,N-Dimethylamino)propyl]isothiourea (dimaprit), has been shown to be a highly specific histamine H2-receptor agonist. Parallel line assays showed that in vitro at H2-receptors it had approximately 17.5% the activity of histamine on the rat uterus and 71% on the guinea-pig right atrium, with similar maximal responses; it had less than 0.0001% the activity of histamine on H1-receptors. Dimaprit stimulated gastric acid secretion in the rat, dog and cat in which it had, respectively, approximately 19,58 and 400-500% the activity of histamine. In the dog and cat the maximum secretory response to dimaprit was significantly greater than that obtained to histamine. The H2-receptor specificity of dimaprit in causing depressor and vasodilator effects was also demonstrated in the cat, in which it had 18-20% of the H2-receptor activity of histamine. Dimaprit should prove to be a very useful tool in studies examining the role of histamine in physiology and pathology. The absence of marked cardiovascular effects at doses maximal for the stimulation of gastric acid secretion, as seen in the cat studies, could lead to this compound being of value as a diagnostic agent in the measurement of maximal acid secretory capacity.