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.

Pharmacological characterization of the human histamine H2 receptor stably expressed in Chinese hamster ovary cells

“…Moreover, recently, a role for the H2 receptor has been suggested in some neurological diseases (Kaminsky et al, 1990;Deutsch et al, 1993;Martinez-Mir et al, 1993), indicating that CNSactive H2 ligands might also have therapeutic potential. Due to these perspectives, the search for more potent and selective H2 receptor agents still continues and has, for instance, recently resulted in the development of the new and highly specific H2 receptor agonists, amthamine and amselamine (Eriks et al, 1991;Timmerman, 1992;Van der Goot et al, unpublished observations).…”