Syntheses are described for all the mono- and some di- and trimethylhistamines. New methods are given for the known Npi, Ntau-, Nalpha-, 2-, and 4-methylhistamines and for the novel compounds, beta-methyl-, 4,Nalpha-dimethyl-, and 4,Nalpha,Nalpha-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 Nalpha positions than elsewhere in the histamine molecule and that receptor binding is substantially retained with a methyl substituent in these positions. Thus, for the design of potential antagonists, two sites are identified as being worthwhile exploring for the introduction of lipophilic substituents.

Based on an analogy with adrenergic j-receptor stimulants and their antagonists, several aminoethylimidazo[l,2nlpyridines and -imidazo[1.5-aJpyridines including their tetrahvdro derivatives were synthesized as potential histamine Ha-receptor antagonists. Neither agonist nor antagonist activity at H2 receptors was detected. 2-(2-Aminoethyl)imidazo[l,2-a]pyridines were, however, found to be moderately active Hi-receptor agonists.