Synthesis and Histamine H 3 and H 4 Receptor Activity of Conformationally Restricted Cyanoguanidines Related to UR‐PI376

Recently, we identified highly potent agonists of the human histamine H 4 receptor (hH 4 R) among a series of imidazolylbutylcyanoguanidines. Aiming at improved selectivity for the hH 4 R relative to the H 3 receptor (hH 3 R), 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 hH 3 R and hH 4 R (investigated in [ 35 S]GTPγS binding assays using Sf9 insect cell membranes expressing hH x R subtypes). By contrast, the incorporation of a more flexible cyclohexane‐1,4‐diyl linker resulted in EC 50 or K B values ≥110 nM at hH 4 R and hH 3 R. Quality of action, potency and receptor subtype selectivity of the investigated compounds depend on the stereochemistry: Cis ‐configured diastereomers prefer the hH 4 R and are partial agonists, whereas trans ‐isomers are antagonists at the hH 4 R. At the hH 3 R 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 hH 4 R agonists relative to the hH 3 R.