Synthesis and histamine H3 and H4 receptor activity of conformationally restricted cyanoguanidines related to UR-PI376

Abstract

Recently, we identified highly potent agonists of the human histamine H4 receptor (hH4R) among a series of imidazolylbutylcyanoguanidines. Aiming at improved selectivity for the hH4R relative to the H3 receptor (hH3R), the flexible tetramethylene linker connecting imidazole ring and cyanoguanidine group was replaced by conformationally restricted carbocycles. Introduction of a para- or a meta-phenylene spacer yielded only very weakly active compounds at both hH3R and hH4R (investigated in [35S]GTPγS binding assays using Sf9 insect cell membranes expressing hHxR subtypes). By contrast, the incorporation of a more flexible cyclohexane-1,4-diyl linker resulted in EC50 or KB values ≥ 110 nM at hH4R and hH3R. Quality of action, potency and receptor subtype selectivity of the investigated compounds depend on the stereochemistry: cis-configured diastereomers prefer the hH4R and are partial agonists, whereas trans isomers are antagonists at the hH4R. At the hH3R the trans diastereomers are superior to the cis-isomers by a factor of 10. The results on imidazolylcycloalkylcyanoguanidines suggest that variation of ring size and optimization of the stereochemistry may be useful to increase the potency and selectivity of hH4R agonists relative to the hH3R.