Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists.
Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50 = 7.47, alpha = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using membrane preparations of hH(x)R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pKB = 8.42, >300-fold selectivity over the other HR subtypes).
Department of Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitatsstrasse 31, D-93053 Regensburg, Germany.
Patrick
P
Igel
Roland
R
Geyer
Andrea
A
Strasser
Stefan
S
Dove
Roland
R
Seifert
Armin
A
Buschauer
D000818:Animals; D055808:Drug Discovery; D019791:Guanidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D017442:Histamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007553:Isotope Labeling; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011968:Receptors, Histamine / Q000737:chemistry / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D006146:Guanidines; C418607:HRH4 protein, human; D017442:Histamine Agonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C409964:sulfonylguanidine; D006160:Guanosine Triphosphate; D019791:Guanidine; C004711:dicyandiamido