In guinea pig ventricular myocardium the rank order was 2-(3-iodo-), 2-(3-bromo-), histamine, 2-(3-chloro-), and 2-(3-fluorophenyl)histamine showing better correlation with the lipophilicity of the derivatives than in vascular tissue (order of lipophilicity: 2-triFMPH >2-IPH >2-BPH >2-CPH >2-FPH >>2-PH). Displacement of the radioligand binding to myocardial H1 receptor by the above drugs is (except for 2-(3-fluorophenyl)histamine), better fitted to a two-site model. 2-phenylhistamine, which acted as a moderate agonist in functional studies, displaced the radioligand in a monophasic manner and was the weakest displacer of specific radioligand binding in both model systems (pKi = 5.76--vascular and 5.57--cardiac tissue). The agonistic nature of the halogenated 2-phenylhistamine derivatives was confirmed on the molecular level, since their interaction with the H1 receptor is regulated by guanine nucleotides. GTP (0.1 mM) significantly lowered the affinities of all tested halogenated 2-phenylhistamines and histamine for H1 receptor binding site converting biphasic displacement curves, to monophasic ones, whereas GTP had no effect on the affinity of 2-PH. The results of this study support the conclusions that bovine vascular and guinea pig myocardial histamine H1 receptors differ in their molecular properties.
Selective and potent H1 receptor agonists of 2-phenylhistamine class can discriminate between vascular and cardiac receptor.