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.
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
M
M
Muramatsu
H
H
Hirose-Kijima
H
H
Aihara
S
S
Otomo
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D002927:Cimetidine / Q000494:pharmacology; D015738:Famotidine / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D013268:Stimulation, Chemical; D013997:Time Factors
D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; D011970:Receptors, Histamine H2; C063924:IT 066; D015738:Famotidine; D002927:Cimetidine