Structure-activity characterization of an H2-receptor antagonist, 3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-++ +butenylamino]- 3-cyclobutene-1,2-dione hydrochloride (T-066), involved in the insurmountable antagonism against histamine-induced positive chronotropic action in guinea pig atria.

IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino]-3-cyclobutene-1,2-dione hydrochloride), an H2-receptor antagonist, shows highly potent, time-dependent, and irreversible antagonism at H2-receptors. We identified the structurally important parts of IT-066 involved in its interaction with the H2-receptor, and explored its unique mode of action by investigating the H2-receptor blocking action of IT-066 and related compounds in guinea pig isolated atria. IT-066 is structurally divided into three different parts: a tertiary amine and hydrophobic group, a connecting carbon chain, and a polar group. Though the replacement of its pyridine ring with a benzene ring maintained the mode of the H2-receptor blocking action of IT-066, the oxidation of the piperidine ring completely attenuated this blocking action. By replacing the connecting carbon chain of IT-066, cis-2-butene, with butane, trans-2-butene, or 2-butyne, the irreversible antagonism disappeared and the potency was reduced. On the other hand, BMY25368, whose connecting carbon chain is trimethylene, showed irreversible antagonism comparable to that of IT-066. Hydrolysis of the polar group of IT-066 completely attenuated the H2-receptor blocking activity. Among the compounds tested, only the compound that had 3,4-diamino-3-cyclobutene-1,2-dione as a polar group showed time-dependent and insurmountable H2-receptor blocking action. These data suggest the importance of the following structural features of IT-066: the piperidine ring of IT-066 and -NH2 in its polar group are essential for the interaction with the H2-receptor; and the 3,4-diamino-3-cyclobutene-1,2-dione group and the connecting carbon chain of IT-066 are crucial for determining the irreversibility of H2-receptor blocking action, though the connecting carbon chain is replaceable with another chain with appropriate length and configuration.