2-SUBSTITUTED HISTAMINES WITH G-PROTEIN-STIMULATORY ACTIVITY

The cationic-amphiphilic 2-substituted histamines, 2-(3-chlorophenyl)h istamine 2-[2-(3-chlorophenyl)-1H-imidazol-4-yl]ethanamine) and 2-(2-c yclohexylethyl)histamine, activate pertussis toxin-sensitive guanine n ucleotide-binding proteins (G-proteins) of the G(i)-subfamily by a rec eptor-independent mechanism. We studied structure-activity relationshi ps of 2-substituted histamine derivatives for this G-protein activatio n using six known and 12 newly synthesized compounds. Elongation of th e alkyl chain between imidazole and the ring system enhanced the poten cy and efficiency of substances in activating high-affinity GTP hydrol ysis, ie the enzymatic activity of G-protein alpha-subunits, in membra nes of HL-60 leukemic cells. Cyclopentyl-, cyclohexyl- and norbornyl-s ubstituted histamines were more effective and potent than phenyl-subst ituted 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 import ant determinants for receptor-independent G-protein activation by 2-su bstituted histamines. With respect to histamine H-1-receptors, most of the substances studied displayed weak antagonistic activity.