title: Synthesis and dual histamine H₁ and H₂ receptor antagonist activity of cyanoguanidine derivatives.
abstract: 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, 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.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health sciences, UAE University, Al-Ain, P.O. Box 17666, UAE. bassem.sadek@uaeu.ac.ae.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.forename: Rudi
authors.initials: R
authors.lastname: Alisch
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
mesh_terms: D000818:Animals; D002927:Cimetidine / Q000031:analogs & derivatives / Q000737:chemistry; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry*; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry; D011738:Pyrilamine / Q000737:chemistry
chemical_list: D006146:Guanidines; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D010880:Piperidines; D002927:Cimetidine; C023990:tiotidine; D011738:Pyrilamine; C004711:dicyandiamido; C053742:roxatidine acetate