Potential histamine H2-receptor antagonists. 3. Methylhistamines

Abstract

Syntheses are described for all the mono- and some di- and trimethylhistamines. New methods are given for the known N.pi., N.tau.-, N.alpha.-, 2- and 4-methylhistamines and for the novel compounds, .beta.-methyl-, 4,N.alpha.-dimethyl- and 4,N.alpha.,N.alpha.-trimethylhistamines. Agonist activities are reported for stimulation of histamine H1 (guinea-pig ileum) and H2 (rat gastric acid secretion) receptors. H2-Receptor agonist activities indicate that a methyl group is more readily accommodated at the 4 and N.alpha. positions than elsewhere in the histamine molecule and that receptor binding is substantially retained with a methyl substituent in these positions. For the design of potential antagonists, 2 sites are identified as being worthwhile exploring for the introduction of lipophilic substituents.