Structure-Activity Relationships of Histamine H2 Receptor Ligands+

Abstract

Recent research on histamine H2 receptor agonists was focused on quantitative structure-activity relationships and receptor models explaining the activity of imidazolylpropylguanidines. Their selectivity for guinea pig vs. human isoforms was investigated using H2 receptor-Gsalpha fusion proteins and attributed to amino acid differences in transmembrane domains 1 and 7. New antagonists result from approaches to improve pharmacokinetic properties and to design hybrid drugs which additionally have gastroprotective or anti H. pylori activity.

Effects of Impromidine‐ and Arpromidine‐Derived Guanidines on Recombinant Human and Guinea Pig Histamine H1 and H2 Receptors.

“…H 2 R agonists are interesting potential drugs for the treatment of various human disorders including acute heart failure, acute promyelocytic leukemia and inflam- matory diseases [4,5]. In order to come closer to these ambitious goals, it is necessary to develop highly potent and efficacious hH 2 R agonists.…”

“…Finally, with a lag period of almost a decade, it became clear that two defined amino acid differences in transmembrane domains 1 and 7 between hH 2 R and gpH 2 R account for the pharmacological differences [9]. These advances rekindled interest in the development of H 2 R agonists [5,10]. ARP, bearing a 4-fluorophenyl group at the guanidino group, is one of the most potent hH 2 R agonists known so far, but it is still only a partial agonist and less potent than at gpH 2 R (Table 1) [9].…”

“…The H 1 R couples to G q -proteins, the H 2 R couples to G s -proteins, and the H 3 R and H 4 R couple to G i /G o -proteins. We are particularly interested in the development of H 2 R agonists that could be used for the treatment of acute heart failure, acute promyelocytic leukemia, and inflammatory diseases [4,5]. H 2 R agonists are divided into two classes.…”

“…Highest potency is found for compounds with a three-membered instead of a two-membered carbon chain as in histamine connecting the imidazole ring and the basic group. The corresponding partial structures of impromidine and histamine are considered as functionally equivalent groups that are important for the receptor activation i. e., the guanidino group and the imidazolylpropyl moieties of IMP and ARP are supposed to form similar interactions with the H 2 R as the amino group and imidazole groups of HA, respectively [5,9]. Additionally, the 2-(5-methylimidazol-4-ylmethylthio)ethyl moiety of IMP and the 3-(4-fluorophenyl)-3-(2-pyridyl)propyl substituent of ARP interact with a pocket formed by multiple residues in transmembrane domains 3, 6, and 7 [9].…”

The effect of histamine on kidney by fasting in rats

“…The importance of histamine has been demonstrated in gastric acid secretion, contraction of smooth muscle, neurotransmission, wound repair, embryogenesis, hematopoiesis, allergic skin reactions and malignant growths. Additionally, histamine has been found to function in the auto, para and endocrine pathways through four types of histamine receptors (H1, H2, H3 and H4), while also signaling via different signal-transduction pathways (8,9,10,11). Histamine has also been shown to enhance Ca ++ entry into several tissues, including vascular endothelium, bronchial smooth muscles, brain and kidneys (4,5,6,12).…”