H. Detert et al., 2-ALKYL-SUBSTITUTED HISTAMINES AND HYDROXYETHYLIMIDAZOLES WITH G-PROTEIN-STIMULATORY ACTIVITY, European journal of medicinal chemistry, 31(5), 1996, pp. 397-405
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.