Ciproxifan and chemically related compounds are highly potent and selective histamine H3-receptor antagonists

Abstract

We determined the affinities of five newly synthesized histamine H₃-receptor antagonists in an H₃-receptor binding assay and their potencies in a functional H₃-receptor model. Furthermore, we determined their potencies in a histamine H₂- and H₁-receptor model. The compounds differ from histamine in that the ethylamine side chain is replaced by an aryl-substituted propyloxy chain and they differ from one another by varying substituents of the aryl rest. Iodoproxyfan, a highly potent and selective antagonist at H₃ receptors, is structurally related to these five compounds.

The specific binding of [³H]-N ^α-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the five compounds at pK _i values ranging from 8.24 to 9.27. Inhibition by histamine of the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [³H]noradrenaline was antagonized by all compounds and the concentration-response curve was shifted to the right with apparent pA ₂ values ranging from 7.78 to 9.39. The five compounds under study possess negligible potencies at histamine H₂ and H₁ receptors studied in the guinea-pig right atrium and ileum, respectively (pD’₂ or pK _p values ≤5.2).

The present paper shows that the five compounds under study possess high affinities and potencies at histamine H₃ receptors, four out of the five compounds in this respect being equipotent with iodoproxyfan. Like iodoproxyfan, the five compounds show an at least 1000-fold selectivity for H₃ as compared to H₂ and H₁ receptors.