Time-dependent interaction of a new H2-receptor antagonist, IT-066, with the receptor in the atria of guinea pig.

3-Amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino]-3-cyclobutene-1,2-dione hydrochloride (IT-066) showed a highly potent and long lasting H2-receptor blocking action in guinea pig atria. The inhibitory effect of IT-066 on the histamine-induced positive chronotropic response increased concentration- and time-dependently. A short period of treatment with IT-066 shifted the concentration-response curve of histamine to the right in parallel, without decreasing the maximal response to histamine. With prolongation of the treatment, the concentration-response curve shifted further to the right with time-dependent suppression of the maximal response to histamine. The inhibitory effect of IT-066 was irreversible. The dissociation constant for histamine (KA) was not changed by prolongation of the time of incubation with IT-066. The dissociation constant for IT-066 (KB) was decreased with the prolongation of the treatment. Kinetic analysis of the time-dependent inhibition showed a two-step reaction: the first was reversible and the second was irreversible. Preincubation of the atria with ranitidine, however, protected the H2-receptor from the apparently irreversible antagonism of IT-066. These results suggest that IT-066 has a time-dependent and irreversible interaction with the H2-receptor and that the interaction may be responsible for the potent and long lasting H2-receptor blocking action of IT-066.