Our purpose is to more fully understand the geometrical requirements of the histamine H2-receptor antagonists and the H2-receptor site. Specifically, syntheses of macrocyclic analogues of H2-receptor antagonists would be pursued. Such compounds would be locked into cis folded conformations and would provide insight into the nature of the interaction of antagonists with the H2-receptor site as assessed from biological data. The efficacy of these compounds as H2-receptor antagonists would be ascertained by pharmacologic protocols involving H2-specific tissues such as gastric mucosa, guinea pig right atrium, and rat uterus. Relative binding affinities (pA2) will be calculated from dose-response curves exhibiting competitive antagonism of histamine H2 sites by the synthesized compounds. Conformational analyses of these macrocyclic compounds would be studied by the use of molecular mechanics and molecular orbital techniques as well as spectroscopic and crystallographic methods. The pharmacological actions of histamine are considered to be mediated by at least two distinct classes of receptor, designated H1 and H2, distinguished by the action of specific histamine antagonists that selectively block histamine responses. Histamine evidently plays an important role on the gastric mucosa, smooth muscle, myocardium, adrenal medulla, and certain neural processes, and may involve cyclic AMP as a second messenger in these pharmacological actions. Histamine H2-receptor antagonists are widely used as effective inhibitors of gastric acid secretion in the treatment of duodenal ulcers and related conditions. Histamine receptors are also important in controlling heart rate. It appears as if H2 receptors are responsible for mediating histamine-induced idioventricular tachyarrhythmia. This may have important implications for the treatment of ventricular arrhythmia caused by histamine release. At present, the geometrical requirements of histamine H2-receptor antagonists are ambiguous. Neither the binding site geometry nor the requirements for efficient absorption of the antagonists are understood. Macrocyclic analogues of histamine H2-receptor antagonists would be useful in understanding the nature of interaction of antagonists with H2-receptor sites, and would provide additional information as to the geometrical and conformational requirements of these drugs. Apparent conformation-relative binding affinity relationships should provide insight for further histamine H2-receptor investigations.