2-ALKYL-SUBSTITUTED HISTAMINES AND HYDROXYETHYLIMIDAZOLES WITH G-PROTEIN-STIMULATORY ACTIVITY

Cationic-amphiphilic 2-substituted histamines activate pertussis toxin -sensitive guanine nucleotide-binding proteins (G-proteins) by a recep tor-independent mechanism. From our recent studies it became apparent that lipophilicity is an important determinant for this G-protein acti vation, but the influence of basicity remained unknown. We prepared se ven novel 2-alkyl-substituted histamines and five novel 2-alkyl-substi tuted hydroxyethylimidazoles and studied their effects on high-affinit y guanosine triphosphate (GTP) hydrolysis in membranes of the human le ukemia cell line, HL-60. 2-Octylhistamine was found to be the most eff ective GTPase activator among 2-substituted histamines presently avail able (150% stimulation above basal), and 2-tetradecylhistamine is the most potent substance in this regard (pEC(50) = 5.9). Branching of the alkyl chain and the introduction of an ether group adversely affected GTPase activation. Compared to a phenyl ring, a bulky adamantyl spher e enhanced G-protein-stimulatory activity. In the case of 2-(3-bromoph enyl)histamine, 2-adamantylhistamine and 2-(3-phenylpropyl)histamine, replacement of the aminoethyl group by a hydroxyethyl group at the imi dazole greatly reduced GTPase-activating properties, pointing to the i mportance of the basic domain in the activation process. Unexpectedly, however, in the case of a very lipophilic substituent (heptadecyl cha in) the exchange of the aminoethyl group by a hydroxyethyl group had n o substantial inhibitory effect, indicating that the presence of a pri mary amine is not a conditio sine qua non for a substance being a rece ptor-independent G-protein activator. Concerning histamine H-1-recepto rs the newly prepared compounds proved to be weak antagonists.