Igel, Patrick and Geyer, Roland and Straßer, Andrea and Dove, Stefan and Seifert, Roland and Buschauer, Armin (2009) Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H(4) receptor agonists. Journal of Medicinal Chemistry 52 (20), pp. 6297-6313.
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Other URL: http://pubs.acs.org/doi/full/10.1021/jm900526h?prevSearch=Buschauer&searchHistoryKey=, http://pubs.acs.org/doi/pdf/10.1021/jm900526h, http://www.ncbi.nlm.nih.gov/pubmed/19791743?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
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, α = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB = 6.00, α = -0.28), as determined in steady-state GTPase assays using membrane preparations of hHxR-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 highly potent and selective hH3R inverse agonist (pKB = 8.42, > 300 fold selectivity over the other HR subtypes).
|Date:||30 September 2009|
|Additional information (public):||Supporting Information available online|
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann formerly Prof. Seifert)
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Keywords:||acylguanidine; cyanoguanidine; histamine H3 receptor; histamine H4 receptor; UR-PI376; UR-PI97|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Owner:||Prof. Armin Buschauer|
|Deposited On:||15 Sep 2009 11:32|
|Last Modified:||15 Oct 2009 06:31|