- 2-Substituted histamines with G-protein-stimulatory activity
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The cationic-amphiphilic 2-substituted histamines, 2-(2-chlorophenyl)histamine (2-ethanamine) and 2-(2-cyclohexylethyl)histamine, activate pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins) of the Gi-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 Gi/Go-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.
- Detert, H.,Hagelueken, A.,Seifert, R.,Schunack, W.
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p. 271 - 276
(2007/10/02)
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