N(G)-Acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent

Abstract

3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H3 receptor (hH3R) and human histamine H4 receptor (hH4R). With the aim to increase selectivity for the hH4R, the guanidine group in 4 was acylated. N1-Acetyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at hH4R (pEC50: 8.31, α: 1.00), possessing more than 1000- and 100-fold selectivity relative to hH1R and hH2R, respectively, and possessing only low intrinsic activity (α: 0.27) at hH3R.