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

Bassem Sadek,Armin Buschauer,Sigurd Elz,Rudi Alisch

doi:10.3390/molecules181114186

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.

Highlights

The biogenic amine histamine mediates its effects via four histamine receptor subtypes, termed H1, H2, H3, and H4 receptors (HxR) [1,2,3]
Numerous pathophysiological responses to histamine released from mast cells and basophils through immunological or non-immunological mechanisms are mediated by the H1R, for instance, vasodilatation via nitric oxide release, increase in capillary permeability, contraction of smooth muscles, e.g., in gut and bronchi
Antagonist activity and restored pronounced H2R antagonism. The affinity at both receptors should be further increased with respect to the development of combined H1R/H2R antihistamine as potential pharmacotherapeutic agents

Summary

Introduction

The biogenic amine histamine mediates its effects via four histamine receptor subtypes, termed H1, H2, H3, and H4 receptors (HxR) [1,2,3]. As an autacoid and neurotransmitter, histamine is involved in numerous physiological and pathophysiological processes. Numerous pathophysiological responses to histamine released from mast cells and basophils through immunological or non-immunological mechanisms are mediated by the H1R, for instance, vasodilatation via nitric oxide release, increase in capillary permeability, contraction of smooth muscles, e.g., in gut and bronchi. The first H1R blockers [7] have been described as “antihistamines” more than 70 years ago, and especially the newer non-sedating H1R antagonists are widely used in the treatment of allergic conditions [7]. Stimulation of gastric acid secretion is the most prominent physiological effect of H2R stimulation. In the 1970s the development of the H2R antagonists revolutionized the treatment of gastric and duodenal ulcers [8]. Histamine can induce cardiovascular effects via H2Rs, e.g., increase in heart rate and cardiac contractility as well as vasodilatation [9]

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