Potential histamine H2-receptor antagonists. 4. Benzylhistamines.

As part of our studies aimed at designing histamine H2-receptor antagonists, the effect on histaminergic activity of introducing benzyl substituents at various positions in the histamine molecule is described. New synthetic methods are reported for the novel 4-benzyl-, beta-benzyl- and 4,N tau-dibenylhistamines and the reported 2-benzylhistamine. The novel N tau-benzylhistamine was synthesized by the versatile route reported by us for the synthesis of N tau-methylhistamine. These benzylhistamines, together with the reported N alpha- and N pi-benzylhistamines, were tested for agonist and antagonist activity at both H1 and H2 receptors. The results obtained indicate that introduction of a benzyl group into the histamine molecule causes a marked reduction in H1- or H2-agonist activity, and none of the compounds showed consistent antagonist activity. Evidently, the sterically demanding benzyl substituent is not easily accommodated in the agonist binding mode and is unable to locate a lipophilic receptor region for potential hydrophobic binding.