Irreversible blockade of responses to a partial agonist acting at the histamine H1-receptor.

N,N-Diethyl-2-(1-pyridyl)-ethylamine (E-2-P) has been shown previously to behave as a simple partial agonist at the histamine H1-receptor of guinea-pig ileum. When isolated longitudinal muscle strips from this preparation were tested with E-2-P before and after blockade with 2-haloalkylamines, it was found that these agents produced an irreversible shift to the right in the dose-response curve without significant depression of the maximum response even at very high antagonist concentrations. Under these circumstances the maximum response to the partial agonist may exceed the maximum response to histamine itself since the latter shows a much diminished maximum response at a very high concentrations of antagonist. These findings are not readily explicable in terms the usual "receptor-reserve' model of the histamine receptor system in ileum. A tentative explanation is provided, involving interaction with the antagonist at more than one site.