ABSTRACT
Burimamide was one of the first compounds reported to antagonize the activation of the histamine H3 receptor by histamine. We have prepared a large series of burimamide analogs by variation of the alkyl spacer length of burimamide from two methylene groups to six methylene groups and also by replacement of the N-methyl group with other alkyl and aryl groups. All analogs are reversible, competitive H3 antagonists as determined on the guinea pig intestine. Elongation of the alkyl chain from an ethylene chain to a hexylene chain results in an increase of the H3 antagonistic activity. The H3 selective pentylene and hexylene analogs of burimamide are about 10 times more potent than burimamide. The N-thiourea substituents, however, have no beneficial influence on the affinity.
Subject(s)
Burimamide/analogs & derivatives , Histamine Antagonists , Thiourea/chemistry , Animals , Burimamide/chemistry , Burimamide/pharmacology , CHO Cells , Cricetinae , Guinea Pigs , In Vitro Techniques , Jejunum/drug effects , Jejunum/metabolismABSTRACT
Burimamide, a histamine H2-receptor antagonist, has been shown to cause pressor responses in pithed rats. The response can be prevented by prior removal of the adrenal glands or by pretreatment with the alpha-adrenoceptor antagonist, phentolamine, 5 mg/kg, suggesting that the pressor response to burimamide is due to release of catecholamines from the adrenal glands. The pressor activity of burimamide has been compared with that of metiamide and two close chemical analogues, methylburimamide and thiaburimamide, in order to identify which chemical features of the compounds are necessary for this activity. Methylburimamide was the most potent pressor agent, followed by burimamide, metiamide and thiaburimamide. The pressor effects (and presumably catecholamine-releasing activities) appear to be related to the basicities of the compounds. We conclude that the release of catecholamines by these histamine H2-receptor antagonists is probably due to their cationic (imidazolium) forms.
