title: Synthesis and histamine H(3) and H(4) receptor activity of conformationally restricted cyanoguanidines related to UR-PI376.
abstract: 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.
authors: Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Germany.
authors: Roland
authors: R
authors: Geyer
authors: Armin
authors: A
authors: Buschauer
mesh_terms: D000818:Animals; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D011968:Receptors, Histamine / Q000737:chemistry; D000074040:Receptors, Histamine H4; D018411:Spodoptera; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; C418607:HRH4 protein, human; D017442:Histamine Agonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C004711:dicyandiamido