The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H2 Receptor Agonists

Bivalent histamine H2 receptor (H2R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by NG-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H2R agonism in GTPase and [35S]GTPγS binding assays at guinea pig (gp) and human (h) H2R-GsαS fusion proteins including various H2R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H1, H3, and H4 receptors. The bivalent ligands are H2R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH2R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H2R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH2 groups) to simultaneously occupy two orthosteric binding sites in H2R dimers are nearly inactive, whereas the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H2R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer.