Potential histamine H2-receptor antagonists. 3. Methylhistamines.

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.