Histamine receptor antagonists structure-activity relationship

Nauta WTh, Rekker RF. Structure-activity relationships of Hj receptor antagonists. In Histamine and anti-Histami-nics. II, Handbook of Experimental Pharmacology. Rocha a Silva M (Ed.). Springer, Berlin, 1978, p. 215. 

Having gained a knowledge of the structure-activity relationships for histamine, the task was now to design a molecule which would be recognized by the H2 receptor, but which would not activate it. In other words, an agonist had to be converted to an antagonist. In order to do that, it would be necessary to alter the way in which the molecule was bound to the receptor. 

STRUCTURE-ACTIVITY RELATIONSHIP All the available Hj-receptor antagonists are reversible competitive inhibitors of the interaction of histamine with Hj receptors. Like histamine, many Hj antagonists contain a substituted ethylamine moiety. Unlike histamine, which has a primary amino group and a single aromatic ring, most Hj antagonists have a tertiary amino group linked by a two- or three-atom chain to two aromatic substituents (e.g., diphenhydramine). 

In the histaminic H2 receptor antagonist series, the classical urea-thiourea-guanidine progression was successfully completed by the use of the V-nitro and V-cyanoguanidines and, later on, by l,l-diamino-2-nitroethylene groups (Fig. 13.19). Cyano amidines and carbamoyl amidines were also used, and structure-activity relationship patterns were rationalized in terms of dipole moment orientation of related bioisosteric groups. ... 

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