NEW INHIBITORS OF HISTAMINE-N-METHYLTRANSFERASE

A variety of histamine agonists, antagonists and their analogs were tested for their ability to inhibit histamine-N-methyltransferase. In earlier studies, we had shown that the enzyme is inhibited noncompetitively by the histamine H2-receptor agonist, Dimaprit, and we had suggested that the enzyme possessed an inhibitory site with an affinity for both Dimaprit and histamine. The most potent inhibitors had, in addition to a side chain ammonium group, a thiourea or imidazole group which, like the imidazole group of histamine, is capable of prototropic tautomerism. The H1-receptor agonists, 2-pyridyl-β-ethylamine and 2-thiazolyl-β-ethylamine, which do not undergo prototropic tautomerism, were only weakly inhibitory. There was no correlation, however, between pharmacological and inhibitory activity. The most potent inhibitor (Ki∼ 10-6 M) was a Dimaprit analog, SKF 91488, which has no histamine agonist activity. SKF 91488, therefore, may be especially useful in studies of histamine metabolism. © 1979.