2,4-Diaminopyrimidines as histamine H4 receptor ligands—Scaffold optimization and pharmacological characterization

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…The number of H 3 receptor isoforms possible Vollinga et al (1994). Sharif et al (1996) Data from Harada et al (1983); Gantz et al (1991b); Leurs et al (1994aLeurs et al ( , 1995b; Sharif et al (1996) d Data from Ligneau et al, 2000;Liu et al, 2001b;Morse et al, 2001;Zhu et al, 2001;O'Reilly et al, 2002;Esbenshade et al, 2003;Thurmond et al, 2004Thurmond et al, , 2014aLim et al, 2005;Gbahou et al, 2006;Ligneau et al, 2007;Nagase et al, 2008;Zhao et al, 2008;Deml et al, 2009;Sander et al, 2009;Mowbray et al, 2011;Rossbach et al, 2011;Appl et al, 2012;Shin et al, 2012;Andaloussi et al, 2013;Savall et al, 2014 Fig. 10).…”

Histamine Downregulates the Th1-Associated Chemokine IP-10 in Monocytes and Myeloid Dendritic Cells

“…0.5 to 1 × 10 5 mDC and 3 × 10 5 monocytes were seeded per well in 96-well plates and were preincubated overnight with histamine (Alk-Scherax) or one of the histamine receptor agonists (H 1 R agonist 2-pyridylethylamine and H 2 R agonist amthamine; both Tocris Bioscience, Bristol, UK; the H 4 R agonist ST1006 was synthesized by Holger Stark, Goethe University, Frankfurt am Main, Germany, as published previously [15] ). Afterwards cells were stimulated for 24 h with 10 -5 M poly I:C, then cell-free supernatants were harvested and analyzed for IP-10 content using a commercially available ELISA according to the manufacturer's protocol (IP-10: R&D Systems).…”

In Silico Characterization of Ligand Binding Modes in the Human Histamine H4 Receptor and their Impact on Receptor Activation

“…[3] We recently reported a series of 2,4-diaminopyrimidines that showed differing functionalities, ranging from partial agonism to inverse agonism, depending on substitution pattern and degree of conformational constriction. [4] Aiming to clarify the binding mode within this class of structurally highly related compounds and the resulting receptor activation mechanisms we performed molecular dynamics (MD) simulations with the partial agonist ST-989 (maximal efficacy, E max = 24 % related to maximal response of histamine as full agonist) and the inverse agonist ST-1012 (E max = À111 % related to maximal inhibition of constitutive activity by thioperamide as a reference inverse agonist; Scheme 1). Both ligands displayed potencies in the same concentration range (pEC 50~7 .5).…”

“…Both ligands displayed potencies in the same concentration range (pEC 50~7 .5). [4] GPCRs are allosteric proteins that respond to small molecules by conformational changes, thereby affecting large protein-protein interactions. Basically, two receptor conformations, the inactive (R) and the active (R*) state, are distinguished.…”