A selective human H4-receptor agonist:: (-)-2-cyano-1-methyl-3-{(2R,5R)-5-[1H-imidazol-4(5)-yl]tetrahydrofuran-2-yl}methylguanidine

A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H-3- and H-4-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H-3-receptor than the H-4-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H-4-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H3-receptor. As such, 3b and 3c are the first selective H-4 receptor agonists.