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.