Taken together the four HRs couple with several different si

Taken together, the four HRs couple with several different signaling pathways modulating various G-proteins (Fig. 1).
Histamine H1R The H1R, including many other biogenic amine receptors, is one of the GPCR family members (see for a complete list e.g. http://www.gpcr.org/7tm/ or http://tools.gpcr.org/visualise/proteinselection) for which a tremendous input with the solved crystal structures has been done so far. In the early 1990s, a significant contribution to targeted research of H1R ligands has been provided by the cloning of the human H1R protein consisting of 487 filgotinib (gene locus 3q25). Specifically synthesized antagonists could then be investigated and characterized in comprehensive binding studies on various species. Furthermore, the X-ray crystallization of H1R has succeeded in 2010 with the slightly modified and stabilized mutant human H1R in complex with the first generation H1R antagonist doxepin (11) (Shimamura et al., 2011). Interestingly, it has been found that the binding pocket of doxepin comprises the highly conserved Asp107 in the transmembrane region 3 (TM3) and aromatic residues in TMs 5 and 6, e.g. Phe424, Trp428 and Phe432 (Fig. 2A) (Panula et al., 2015, Shimamura et al., 2011). In addition, it has been shown that the strong hydrophobic interactions of the aromatic moieties of doxepin withTrp428 may inhibit movement of helix 6, which is commonly described of being one of the important features in GPCR activation. Moreover, it has been observed that doxepin is capable of binding deeply in the pocket expressed by TM3, 5, and 6. Furthermore, a complementary phosphate-anion binding site was observed and described at the entrance of the ligand-binding pocket and described as a unique feature in the x-ray structure. Accordingly, the phosphate anion was found to be matched with Lys179, Lys191 and His450 and this binding pocket is proposed to be crucial for the interaction with zwitterionic H1R antagonists of the second generation antihistamines (Panula et al., 2015, Shimamura et al., 2011). Consequently, possible interactions of the basic amine with the phosphate can affect the stability of the ligand receptor binding, so that the residence of zwitterionic compounds at the receptor (1/Koff) can be significantly increased (Shimamura et al., 2011). Contrary, understandings of the molecular features governing agonist induced H1R activation await the resolution of an active H1R x-ray structure and presently still rely on molecular modeling and/or mutagenesis studies (Jongejan et al., 2005, Ohta et al., 1994, Sansuk et al., 2010, Strasser et al., 2008). However, histamine is thought to bind the H1R with its protonated ethylamine side chain via Asp107 (Ohta et al., 1994), whereas the imidazole ring is believed to interact with Asn198 and Lys191 (Leurs et al., 1995, Leurs et al., 1994). Also, the protonated side chain with Asp107 allows possibly for the release of Ser3.36 tolerating it to function as a closing switch and to interconnect with Asn7.45 positioned at the receptor in its active state (Jongejan et al., 2005, Panula et al., 2015).
H1R agonists Despite the fact that histamine (1) regulates various physiological and pathophysiological effects via H1Rs, the research area of the corresponding agonistic active compounds has been neglected for a long time (Fig. 3). Interestingly, two major structural elements can be differentiated in the histamine molecule, namely the imidazole ring and the aminoethyl side chain. A diversity of structural modifications in both parts has earlier been described (Gerhard and Schunack, 1980a, Gerhard and Schunack, 1980b, Hepp and Schunack, 1980, Stark and Schubert-Zsilavecz, 2004, Vickers et al., 1982, Walter et al., 2011). Hence, introduction of substituents in the ethylene side chain of histamine has not provided interesting H1R agonists, since methylation of the alpha or beta position leads to reduction of H1R activity (Gerhard and Schunack, 1980a, Gerhard and Schunack, 1980b). Contrary, modification of the imidazole heterocycle of histamine has been revealed to be the most talented approach to develop potent and selective H1R agonists for experimental pharmacological tools studying the properties of the H1Rs (Vickers et al., 1982).