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

Molecules

Bassem Sadek³  Rudi Alisch²  Armin Buschauer¹ 

[1] Institute of Pharmacy, University of Regensburg, University Str. 31, Regensburg D-93053, Germany;Institute of Pharmacy, Free University of Berlin, Königin-Luise-Str. 2-4, Berlin D-14195, Germany;Department of Pharmacology and Therapeutics, College of Medicine and Health sciences, UAE University, Al-Ain, P.O. Box 17666, UAE

关键词: dual H₁/H₂ receptor antagonists;    mepyramine;    roxatidine;    tiotidine;    ranitidine;   

DOI  :  10.3390/molecules181114186

来源: mdpi

【 摘 要 】

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 14–35 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, pK_B 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, pK_B 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.

【 授权许可】

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