Routes to Histamine H2-Agonists

Abstract

In this paper the design, synthesis and primary biological testing of several new H2-agonists are presented. The existing agonists dimaprit and impromidine have been used as starting points. Dimaprit seems to be the only member of its class which is an H2-agonist; close analogues of dimaprit proved to be inactive as H2-agonists. In impromidine the moieties constituting the molecule are considered to play different roles: the unsubstituted imidazole is required for receptor activation, whereas the guanidino and the methyl-substituted imidazole are needed for additional receptor binding. Based on this concept several new and potent impromidine-like H2-agonists were obtained. Using the fastidious nature of dimaprit for H2-agonism, computational approaches lead to the design of 2-aminothiazoles as H2-agonists. Several new H2-agonists, also of the impromidine-type, were obtained. This class of compounds provides not only potent, but also selective (negligible effects on H1- and H3-receptors) H2-agonists.