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The histamine H 4 receptor (H 4 R) has generated excitement as a potential target for the development of novel anti-inflammatory therapies. However, many of its physiological functions are still being uncovered and the development of new pharmacological tools is crucial to help facilitate this work. Previously, indole and benzimidazole piperazines have been described as potent and selective H 4 R antagonists. Using this as a starting point we have identified new indole and benzimidazole oxime piperidines as ligands for the H 4 R. These compounds have a high affinity for the human H 4 R with K i values ranging from 17-53 nM. They also have high to moderate affinity for the H 4 R from mouse, rat, guinea pig, and monkey, but poor affinity for the dog homologue. In addition to the high affinity for the H 4 R, these compounds also exhibit excellent selectivity against other histamine receptors as well as many other receptor targets. These oxime ligands act as agonists of the human H 4 R in transfected reporter systems, although the degree of agonism depends on the system utilized. Agonistic activity was also observed in human eosinophils as evidenced by their ability to induce a shape change in these cells, although the degree of agonism ranges from full agonist to partial agonist depending on the test conditions. In contrast to their activity at the human H 4 R, all of the oxime compounds act as full agonists at the mouse receptor regardless of the test system including the ability to induce a calcium response in mouse bone marrow-derived mast cells. Finally the most selective compound, JNJ 28610244, was shown to induce scratching in mice indicating that it can also function as an agonist in vivo.

Pharmacological characterization of oxime agonists of the histamine H4 receptor