Structure-activity studies with histamine H3-receptor ligands.

Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Some compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side-chain amino group show strong H3-antagonist activity. These have served as leads to provide aryloxyethyl- and aryloxy-propylimidazoles which are potent H3 antagonists of histamine. Structure-activity studies of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea), have explored the the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N'-Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having Ki = 1.5 nM.