Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists

On the basis of the long-known prototypic pharmacophore 3-(1 H -imidazol-4-yl)propylguanidine (SK&F 91486, 2 ), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H 2 receptor (H 2 R) agonists with various alkyl spacers were synthesized. Aiming at increased H 2 R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h / gp / r H 2 R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist ( E max = 88%) and 250 times more potent than histamine (pEC 50 : 8.56 vs 6.16, gp H 2 R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest h H 2 R affinities (p K i : 7.47, 7.33) in binding studies. Dimeric amino(methyl)thiazole derivatives, such as 58 , generated an increased h H 2 R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H 2 R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine h H 4 R ligands.