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Comparison of the Pharmacological Properties of Human and Rat Histamine H3-Receptors David Schnell, Andrea Strasser, Roland Seifert

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Comparison of the Pharmacological Properties of Human and Rat Histamine H3-Receptors David Schnell, Andrea Strasser, Roland Seifert Comparison of the pharmacological properties of human and rat histamine H3-receptors David Schnell, Andrea Strasser, Roland Seifert To cite this version: David Schnell, Andrea Strasser, Roland Seifert. Comparison of the pharmacological properties of human and rat histamine H3-receptors. Biochemical Pharmacology, Elsevier, 2010, 80 (9), pp.1437. 10.1016/j.bcp.2010.07.027. hal-00623303 HAL Id: hal-00623303 https://hal.archives-ouvertes.fr/hal-00623303 Submitted on 14 Sep 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: Comparison of the pharmacological properties of human and rat histamine H3-receptors Authors: David Schnell, Andrea Strasser, Roland Seifert PII: S0006-2952(10)00565-4 DOI: doi:10.1016/j.bcp.2010.07.027 Reference: BCP 10660 To appear in: BCP Received date: 18-5-2010 Revised date: 20-7-2010 Accepted date: 23-7-2010 Please cite this article as: Schnell D, Strasser A, Seifert R, Comparison of the pharmacological properties of human and rat histamine H3-receptors, Biochemical Pharmacology (2010), doi:10.1016/j.bcp.2010.07.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. *Manuscript Comparison of the pharmacological properties of 1 2 3 4 human and rat histamine H3-receptors 5 6 7 8 9 10 David Schnell, Andrea Strasser and Roland Seifert 11 12 13 14 Department of Pharmacology and Toxicology, University of Regensburg, 15 16 17 D-93040 Regensburg, Germany (D. S.) 18 19 20 21 Department of Pharmaceutical/Medicinal Chemistry I, University of Regensburg, 22 23 D-93040 Regensburg, Germany (A. S.) 24 25 26 27 28 Institute of Pharmacology, Medical School of Hannover, 29 30 D-30625 Hannover, Germany (R. S.) 31 32 33 34 Corresponding author: 35 36 37 Dr. Roland Seifert, Institute for Pharmacology, Medical School of Hannover, Carl-Neuberg- 38 39 Str. 1, D-30625 Hannover, Germany; Phone: +49-511-532-2805; Fax: +49-511-532-4081; e- 40 41 mail, [email protected] 42 43 44 45 46 Classification: Neuropharmacology 47 48 Accepted Manuscript 49 50 Abbreviations used: GPCR, G protein-coupled receptor; GTPS, guanosine 5’-[- 51 52 thio]triphosphate; h, human; r, rat; β2AR, β2-adrenoceptor; H3R, histamine H3-receptor, H4R, 53 54 histamine H4-receptor; TM, transmembrane domain; JNJ-7753707, (4-fluorophenyl)(1- 55 methyl-2-an-1H-imidazol-5-yl)methanone; FUB181, 4-(3-(3-(4-chlorophenyl)propoxy)propyl)- 56 57 1H-imidazole; A-304121, (R)-2-amino-1-(4-(3-(4-(cyclopropanecarbonyl)phenoxy)- 58 59 propyl)piperazin-1-yl)propan-1-one; fMLP, N-formyl-L-methionyl-L-leucyl-L-phenylalanine; 60 THIO, thioperamide 61 62 63 1 64 Page 1 of 42 65 ABSTRACT 1 2 Ligand pharmacology of histamine H3-receptors is species-dependent. In previous studies, 3 4 two amino acids in transmembrane domain 3 (TM III) were shown to play a significant role. In 5 6 this study, we characterized human and rat histamine H -receptors (hH R and rH R, 7 3 3 3 8 9 respectively), co-expressed with mammalian G proteins in Sf9 insect cell membranes. We 10 11 compared a series of imidazole-containing H3R ligands in radioligand binding and steady- 12 13 state GTPase assays. H3Rs similarly coupled to Gαi/o-proteins. Affinities and potencies of the 14 15 agonists histamine, Nα-methylhistamine and R-(α)-methylhistamine were in the same range. 16 17 18 Imetit was only a partial agonist. The pharmacology of imetit and proxifan was similar at both 19 20 species. However, impentamine was more potent and efficacious at rH3R. The inverse 21 22 agonists ciproxifan and thioperamide showed higher potency but lower efficacy at rH3R. 23 24 Clobenpropit was not species-selective. Strikingly, imoproxifan was almost full agonist at 25 26 27 hH3R, but an inverse agonist at rH3R. Imoproxifan was docked into the binding pocket of 28 29 inactive and active hH3R- and rH3R-models and molecular dynamic simulations were 30 31 performed. Imoproxifan bound to hH3R and rH3R in E-configuration, which represents the 32 33 trans-isomer of the oxime-moiety as determined in crystallization studies, and stabilized 34 35 active hH R-, but inactive rH R-conformations. Large differences in electrostatic surfaces 36 3 3 37 38 between TM III and TM V cause differential orientation of the oxime-moiety of imoproxifan, 39 40 which then differently interacts with the rotamer toggle switch Trp6.48 in TM VI. Collectively, 41 42 the substantial species differences at H3Rs are explained at a molecular level by the use of 43 44 novel H R active-state models. 45 3 46 47 48 Accepted Manuscript 49 Key words: active receptor state; histamine H3-receptor; imoproxifan; molecular dynamics 50 51 simulations; Sf9 insect cells 52 53 54 55 56 57 58 59 60 61 62 63 2 64 Page 2 of 42 65 1. INTRODUCTION 1 2 Histamine (HA) exhibits its biological effects through the activation of four different G 3 4 protein-coupled receptors (GPCRs). The histamine H1-receptor (H1R) is associated with 5 6 inflammatory and allergic reactions, e. g. it increases vascular permeability and NO 7 8 9 production [1]. The histamine H2-receptor (H2R) regulates gastric acid production, but also 10 11 shows a positive inotropic effect on the heart [1]. The histamine H3-receptor (H3R) is a 12 13 presynaptic auto- and heteroreceptor, regulating the release of HA and various other 14 15 neurotransmitters in the nervous system, and is involved in important physiological 16 17 18 processes like the sleep-wake cycle, eating behaviour and cognition [2]. The histamine H4- 19 20 receptor (H4R) mediates inflammatory and immunological processes, e. g. chemotaxis of 21 22 eosinophils, mast cells and dendritic cells, but it is also present on neurons mediating HA- 23 24 induced itching [3, 4]. H1R and H2R antagonists have been used as therapeutics for decades, 25 26 H R and H R are still explored and promising new drug targets [5]. 27 3 4 28 29 The H3R was pharmacologically identified in the early 1980s, but cloned almost 20 30 31 years later in 1999 as an orphan GPCR [2]. The reason for this delay was that it only shares 32 33 ~20% homology to the H1R and H2R. The complex gene structure of the human H3R (hH3R) 34 35 gives rise to many possible splice variants. To date about 20 hH R splice variants are known 36 3 37 38 [6], but their function still remains elusive. The H3R displays high constitutive, i. e. ligand- 39 40 independent, activity in many experimental systems [7]. The H3R is one of the very few 41 42 GPCRs for which constitutive activity has also been demonstrated in vivo [8]. 43 44 For the H R it has also been shown that species-differences exist [9, 10]. Fig. 1 45 3 46 47 shows the amino acid sequences of hH3R and rH3R. Although the H3R sequence has a high 48 Accepted Manuscript 49 degree of similarity among species, differences located in key regions of the receptor protein 50 51 account for differences in antagonist affinity [13, 14]. Additionally, splice variants differ in 52 53 composition and expression pattern between species, and there are potential differences in 54 55 56 signal transduction processes between either tissues and/or species [15]. Nevertheless, 57 58 there are still unresolved questions about species differences of the full-length and un- 59 60 61 62 63 3 64 Page 3 of 42 65 spliced H3Rs (445 amino acids), especially regarding the detailed molecular mechanisms 1 2 involved in ligand-receptor interactions. 3 4 In the present study, we systematically compared the pharmacological properties of 5 6 hH R and rH R. Fig. 2 shows the structures of the compounds studied, all of them being 7 3 3 8 9 imidazole-containing ligands. We co-expressed hH3R and rH3R in Sf9 cells together with 10 11 mammalian G proteins in a defined stoichiometry, determined the affinity of ligands in 12 13 radioligand binding studies, and their potency and efficacy in steady-state GTPase assays. 14 15 The baculovirus/Sf9 cell system is very suitable for the analysis of G /G -coupled receptors 16 i o 17 18 and in particular constitutively active receptors, because in Sf9 cells no endogenous Gi/Go- 19 20 proteins or GPCRs with constitutive activity are present. The controlled expression of 21 22 receptor and G proteins in Sf9 cell membranes represents more the physiological situation 23 24 than, for example, the construction of GPCR-Gα fusion proteins, because fusion proteins do 25 26 27 not exist physiologically and the mobility of the G proteins is not restricted in the co- 28 29 expression system. Moreover, the use of very proximal read-outs, like radioligand binding or 30 31 steady-state GTPase assays prevent possible bias in later steps of the signal transduction 32 33 cascade.
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