2-Substituted histamines with G-protein-stimulatory activity

Article abstract of DOI:10.1016/0223-5234(96)88235-3

The cationic-amphiphilic 2-substituted histamines, 2-(2-chlorophenyl)histamine (2-<2-(3-chlorophenyl)-1H-imidazol-4-yl>ethanamine) and 2-(2-cyclohexylethyl)histamine, activate pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins) of the G_i-subfamily by a receptor-independent mechanism.We studied structure-activity relationships of 2-substituted histamine derivatives for this G-protein activation using six known and 12 newly synthesized compounds.Elongation of the alkyl chain between imidazole and the ring system enhanced the potency and efficiency of substances in activating high-affinity GTP hydrolysis, ie the enzymatic activity of G-protein α subunits, in membranes of HL-60 leukemic cells.Cyclopentyl-, cyclohexyl- and norbornyl-substituted histamines were more effective and potent than phenyl-substituted histamines in mediating G-protein activation in HL-60 membranes and in activating reconstituted bovine brain G_i/G_o-proteins.Our data show that the chain length and the type of ring system are important determinants for receptor-independent G-protein activation by 2-substituted histamines.With respect to histamine H₁-receptors, most of the substances studied displayed weak antagonistic activity.