New high affinity H3 receptor agonists without a basic side chain

Abstract In this study, we replaced the basic amine function of the known histamine H 3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H 3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H 3 receptor over the human H 4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1 H -imidazol-4-yl)-pentan-1-ol, is the most potent histamine H 3 receptor agonist (p K i  = 8.0 and pEC 50  = 8.1) with a 320-fold selectivity at the human H 3 receptor over the human H 4 receptor.