Combined histamine H1/H2 receptor antagonists: part I. Pharmacological hybrids with pheniramine- and roxatidine-like substructures.

A series of hybrid compounds combining the pharmacophores of both pheniramine-type histamine H1 receptor antagonists and roxatidine-type H2 receptor antagonists have been synthesized and tested for histamine antagonism at the isolated ileum (H1) and the spontaneously beating right atrium (H2) of the guinea pig. The 'polar group' of the H2 antagonist moiety (cyanoguanidine, nitroethenediamine or urea) and the side chain amino group of the H1 antagonist portion have been linked by a polymethylene spacer or by a piperazine system. The incorporation of a flexible spacer (2-7 methylene groups) resulted in H1 antagonists achieving up to 2.4 times the activity of pheniramine. Depending on the nature of the polar group the highest H2 antagonist potency resides in compounds with spacers ?2 methylene groups. Nitroethenediamine 24c with a seven-membered chain and a chlorpheniramine substructure proved to be approximately equipotent with pheniramine at the H1 and with ranitidine at the H2 receptor (pKB values 7.82 and 7.1, respectively).