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Molecules 2013, 18(11), 14186-14202; doi:10.3390/molecules181114186

Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives

Department of Pharmacology and Therapeutics, College of Medicine and Health sciences, UAE University, Al-Ain, P.O. Box 17666, UAE
Institute of Pharmacy, Free University of Berlin, Königin-Luise-Str. 2-4, Berlin D-14195, Germany
Institute of Pharmacy, University of Regensburg, University Str. 31, Regensburg D-93053, Germany
Author to whom correspondence should be addressed.
Received: 8 October 2013 / Revised: 10 November 2013 / Accepted: 11 November 2013 / Published: 15 November 2013
(This article belongs to the Section Medicinal Chemistry)
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Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 1435 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the “urea equivalent” of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R) and the isolated spontaneously beating right atrium (H2R) of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R 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)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum) and 7.73 (H2R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R) and 6.61 (H2R) 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 H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.
Keywords: dual H1/H2 receptor antagonists; mepyramine; roxatidine; tiotidine; ranitidine dual H1/H2 receptor antagonists; mepyramine; roxatidine; tiotidine; ranitidine

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Sadek, B.; Alisch, R.; Buschauer, A.; Elz, S. Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives. Molecules 2013, 18, 14186-14202.

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