Premedication with a combination of histamine H 1 receptor (H 1 R) and H 2 receptor (H 2 R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H 1 R and H 2 R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H 1 R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H 2 R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H 2 R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H 1 R) and the isolated spontaneously beating right atrium (H 2 R) of the guinea pig. The results indicate that, depending on the nature of the H 2 R antagonist partial structure, the highest H 1 R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl) (25, pK B values: 8.05 (H 1 R, ileum) and 7.73 (H 2 R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pK B values: 8.61 (H 1 R) and 6.61 (H 2 R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H 1 R and H 2 R pharmacophoric moieties with mutually affinity-enhancing properties.

Compounds with combined histamine H1- and H2-receptor antagonist activity were synthesized by connecting H1- and H2-receptor substructures via cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H1-receptor activity compared to single reference compounds. At the guinea-pig right atrium (H2-receptor model) compounds with mepyramine or cyclizine structure are also less active than the single references tiotidine, ranitidine, or lamtidine. Nevertheless substances with a pheniramine like partial structure proved to be potent histamine H2-receptor antagonists at the atrium model (about 27 times more active than cimetidine).

Synthesis and Combined Histamine H1-and H2-Receptor Antagonist Activity of Mepyramine, Pheniramine, and Cyclizine Derivatives with Cyanoguanidine, Urea, and Nitroethenediamine Groups.-Compounds with combined histamine H1-and H2-receptor antagonist activity are synthesized by connecting H1-and H2-receptor substructures using cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H1-receptor activity. H2-receptor model compounds with mepyramine or cyclizine structure are less active than the single references. Nevertheless substances with pheniramine like partial structure (Vb), (Vc), (VIIb) and (VIIc) are potent histamine H2-receptor antagonists.-(SCHULZE, F. R.; ALISCH, R. A.; BUSCHAUER, A.; SCHUNACK, W.; Arch. Pharm. (Weinheim, Ger.) 327 (1994) 7, 455-462; Inst.