Skip to main content

Advertisement

Log in

Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics

Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Antidepressants and antipsychotics affect multiple molecular targets. Consequently, these drugs exhibit not only unique profiles of therapeutic effects but also several undesired effects. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the large family of G protein-coupled receptors and are very important drug targets. All four H x R subtypes are expressed in the CNS. Interactions of lipophilic, blood–brain barrier-penetrating drugs with H x Rs could contribute to therapeutic and unwanted effects. Therefore, we investigated potencies H x R as well as potencies and (inverse) agonistic efficacies of 34 antidepressants and antipsychotics at HxRs in functional assays. We expressed human H x Rs in Sf9 insect cells and conducted radioligand competition binding experiments and functional steady-state GTPase assays. Ligand affinities and potencies were compared with literature data and related to therapeutic reference ranges. Almost all antidepressants and antipsychotics displayed high binding affinities to H1R and behaved as antagonists. The atypical antidepressant trimipramine behaved as a high-affinity/high-potency H2R antagonist (pK i, 7.39; pK B, 7.36; pA 2, 7.55). Docking to an H2R model suggested a probable binding mode. The affinity of antidepressants and antipsychotics for H3R was low. The atypical antipsychotic clozapine, known to induce agranulocytosis, exhibited partial H4R agonism for which docking experiments provided a molecular basis. Clozapine also exhibited H2R antagonism. We observed dissociations between pK i and pK B values as well as between pK i and pIC50 values for H x Rs. Antidepressants and antipsychotics interact differentially with H x Rs. The concept of functional selectivity (also referred to as ligand-specific receptor conformations or biased signaling) explains dissociations between pK i and pK B values as well as differences between pK i and pIC50 values. The H1R antagonism of numerous antidepressants and antipsychotics is very pronounced. The H2R antagonism of trimipramine and partial H4R agonism of clozapine may be clinically relevant. We also discuss the possible role of the H2R antagonism of clozapine for neutropenia/agranulocytosis induced by this compound. Finally, we discuss the methodological, conceptual, and clinical limitations of our study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Abbreviations

pEC50 :

Negative decadic logarithm of the agonist concentration which induces 50% of the maximum stimulation

pIC50 :

Negative decadic logarithm of inverse agonist concentration which induces 50% of the maximum inhibition

E max :

Maximum response relative to histamine (1.00)

DMSO:

Dimethyl sulfoxide

GPCR:

G protein-coupled receptor

h:

Human

gpH2R-GsαS :

Fusion protein of the guinea pig histamine H2R and the short splice variant of G

2AR:

Human β2 adrenoceptor

H1R:

Histamine H1 receptor

H2R:

Histamine H2 receptor

hH2R-GsαS :

Fusion protein of the human histamine H2R and the short splice variant of G

hH3R:

Human histamine H3 receptor

hH4R:

Human histamine H4 receptor

H x R:

Non-specified histamine receptor subtype

TM:

Transmembrane domain

pK B :

Negative decadic logarithm of the inhibition constant of an antagonist/inverse agonist calculated from functional assays (steady-state GTPase assays in our case)

K D :

Equilibrium dissociation constant calculated from radioligand saturation binding assays

pK D :

Negative decadic logarithm of the equilibrium dissociation constant calculated from radioligand saturation binding assays

pK i :

Negative decadic logarithm of the inhibition constant calculated from radioligand competition binding assays

pA 2 :

negative decadic logarithm of the concentration of antagonist that causes a concentration ratio of agonist of r = 2 in a functional assay (steady-state GTPase in our case)

TCA:

Tricyclic antidepressant

RGS protein:

Regulator of G protein signaling protein

References

  • Ahmed MR, Gurevich VV, Dalby KN, Benovic JL, Gurevich EV (2008) Haloperidol and clozapine differentially affect the expression of arrestins, receptor kinases, and extracellular signal-regulated kinase activation. J Pharmacol Exp Ther 325:276–283

    Article  PubMed  CAS  Google Scholar 

  • Anisuzzaman AS, Nishimune A, Yoshiki H, Uwada J, Muramatsu I (2011) Influence of tissue integrity on pharmacological phenotypes of muscarinic acetylcholine receptors in the rat cerebral cortex. J Pharmacol Exp Ther 339:186–193

    Google Scholar 

  • Antell LA, Murabito AS, Karlstadt RG (1989) Depression not associated with cimetidine. Pa Med 92(26):28

    Google Scholar 

  • Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Leucht S (2010) Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 10:CD006633

  • Bakker RA, Schoonus BJ, Smit MJ, Timmerman H, Leurs R (2001) Histamine H1-receptor activation of nuclear factor-κB: roles for Gβγ- and Gαq/11-subunits in constitutive and agonist-mediated signaling. Mol Pharmacol 60:1133–1142

    PubMed  CAS  Google Scholar 

  • Bakker RA, Nicholas MW, Smith TT, Burstein ES, Hacksell U, Timmerman H, Leurs R, Brann MR, Weiner DM (2007) In vitro pharmacology of clinically used central nervous system-active drugs as inverse H1 receptor agonists. J Pharmacol Exp Ther 322:172–179

    Article  PubMed  CAS  Google Scholar 

  • Ballesteros JA, Shi L, Javitch JA (2001) Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure–function analysis of rhodopsin-like receptors. Mol Pharmacol 60:1–19

    PubMed  CAS  Google Scholar 

  • Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G (2004) The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 37:243–265

    Article  PubMed  CAS  Google Scholar 

  • Becker U, Faurschou P, Jensen J, Beck Pedersen P, Ranløv PJ (1983) Efficacy of trimipramine and cimetidine in the treatment of duodenal ulcer. A double-blind comparison. Scand J Gastroenterol 18:137–143

    Article  PubMed  CAS  Google Scholar 

  • Berger M, Gastpar M (1996) Trimipramine: a challenge to current concepts on antidepressives. Eur Arch Psychiatry Clin Neurosci 246:235–239

    Article  PubMed  CAS  Google Scholar 

  • Berstad A, Bjerke K, Carlsen E, Aadland E (1980) Treatment of duodenal ulcer with antacids in combination with trimipramine or cimetidine. Scand J Gastroenterol Suppl 58:46–52

    PubMed  CAS  Google Scholar 

  • Billings RF, Tang SW, Rakoff VM (1981) Depression associated with cimetidine. Can J Psychiatry 26:260–261

    PubMed  CAS  Google Scholar 

  • Blum AL (1985) Therapeutic approach to ulcer healing. Am J Med 79:8–14

    Article  PubMed  CAS  Google Scholar 

  • Chao ZC, Uetrecht JP (1995) Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to the cells. J Pharmacol Exp Ther 275:1476–1483

    Google Scholar 

  • Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K i) and the concentration of inhibitor which causes 50 per cent inhibition (I 50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Article  PubMed  CAS  Google Scholar 

  • Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318:1258–1265

    Article  PubMed  CAS  Google Scholar 

  • Connelly WM, Shenton FC, Lethbridge N, Leurs R, Waldvogel HJ, Faull RL, Lees G, Chazot PL (2009) The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br J Pharmacol 157:55–63

    Article  PubMed  CAS  Google Scholar 

  • Copsel S, Garcia C, Diez F, Vermeulem M, Baldi A, Bianciotti LG, Russel FGM, Shayo C, Davio C (2011) Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem 286:6979–6988

    Article  PubMed  CAS  Google Scholar 

  • Costa T, Lang J, Gless C, Herz A (1990) Spontaneous association between opioid receptors and GTP-binding regulatory proteins in native membranes: specific regulation by antagonists and sodium ions. Mol Pharmacol 37:383–394-

    PubMed  CAS  Google Scholar 

  • Crowder MK, Pate JK (1980) A case report of cimetidine-induce depressive syndrome. Am J Psychiatry 137:1451

    PubMed  CAS  Google Scholar 

  • Dam Trung Tuong M, Garbarg M, Schwartz JC (1980) Pharmacological specificity of brain histamine H2 receptors differs in intact cells and cell-free preparations. Nature 287:548–551

    Article  PubMed  CAS  Google Scholar 

  • Deml K-F, Beermann S, Neumann D, Straßer A, Seifert R (2009) Interactions of histamine H1-receptor agonists and antagonists with the human histamine H4-receptor. Mol Pharmacol 76:1019–1030

    Article  PubMed  CAS  Google Scholar 

  • Fitzsimons J, Berk M, Lambert T, Bourin M, Dodd S (2005) A review of clozapine safety. Expert Opin Drug Saf 4:731–744

    Article  PubMed  CAS  Google Scholar 

  • Flanagan RJ, Dunk L (2008a) Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol Clin Exp 23:27–41

    Article  CAS  Google Scholar 

  • Flanagan RJ, Dunk L (2008b) Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 23(Suppl 1):27–41

    Google Scholar 

  • Galandrin S, Bouvier M (2006) Distinct signalling profiles of β1 and β2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol Pharmacol 70:1575–1584

    Article  PubMed  CAS  Google Scholar 

  • Gantz I, DelValle J, Wang L, Tashiro T, Munzert G, Guo Y, Konda Y, Yamada T (1992) Molecular basis for the interaction of histamine with the histamine H2 receptor. J Biol Chem 267:20840–20843

    PubMed  CAS  Google Scholar 

  • Gespach C, Saal F, Cost H, Abita JP (1982) Identification and characterization of surface receptors for histamine in the human promyelocytic leukemia cell line HL-60. Comparison with human peripheral neutrophils. Mol Pharmacol 22:547–553

    PubMed  CAS  Google Scholar 

  • Ghorai P, Kraus A, Keller M, Goette C, Igel P, Schneider E, Schnell D, Bernhardt G, Dove S, Zabel M, Elz S, Seifert R, Buschauer A (2008) Acylguanidines as bioisosteres of guanidines: N G-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists. J Med Chem 51:7193–7204

    Article  PubMed  CAS  Google Scholar 

  • Gierschik P, Sidiropoulos D, Steisslinger M, Jakbos KH (1989) Na+ regulation of formyl peptide receptor-mediated signal transduction in HL 60 cells. Evidence that the cation prevents activation of the G-protein by unoccupied receptors. Eur J Pharmacol 172:481–492

    Article  PubMed  CAS  Google Scholar 

  • Green JP, Maayani S (1977) Tricyclic antidepressant drugs block histamine H2 receptor in brain. Nature 269:163–165

    Article  PubMed  CAS  Google Scholar 

  • Gutteck U, Rentsch KM (2003) Therapeutic drug monitoring of 13 antidepressant and five neuroleptic drugs in serum with liquid chromatography–electrospray ionization mass spectrometry. Clin Chem Lab Med 41:1571–1579

    Article  PubMed  CAS  Google Scholar 

  • Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL (1997) International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 49:253–278

    PubMed  CAS  Google Scholar 

  • Hui WM, Lam SK, Lok AS, Ng MM, Lai CL (1992) Maintenance therapy for duodenal ulcer: a randomized controlled comparison of seven forms of treatment. Am J Med 92:265–274

    Article  PubMed  CAS  Google Scholar 

  • Ito C, Morisset S, Krebs MO, Olié JP, Lôo H, Poirier MF, Lannfelt L, Schwartz JC, Arrang JM (2000) Histamine H2 receptor gene variants: lack of association with schizophrenia. Mol Psychiatry 5:159–164

    Article  PubMed  CAS  Google Scholar 

  • Johnson J, Bailey S (1979) Cimetidine and psychiatric complications. Br J Psychiatry 134:315–316

    Article  PubMed  CAS  Google Scholar 

  • Jongejan A, Lim HD, Smits RA, de Esch IJ, Haaksma E, Leurs R (2008) Delineation of agonist binding to the human histamine H4 receptor using mutational analysis, homology modeling, and ab initio calculations. J Chem Inf Model 48:1455–1463

    Article  PubMed  CAS  Google Scholar 

  • Jönsson KA, Eriksson SE, Kagevi I, Norlander B, Bodemar G, Walan A (1984) No detectable concentrations of oxmetidine but measurable concentrations of cimetidine in cerebrospinal fluid (CSF) during multiple dose treatment. Br J Clin Pharmacol 17:781–782

    PubMed  Google Scholar 

  • Kagevi I, Wahlby L (1985) CSF concentrations of ranitidine. Lancet 1:164–165

    Article  PubMed  CAS  Google Scholar 

  • Kagevi I, Thorhallsson E, Wahlby L (1987) CSF concentrations of famotidine. Br J Clin Pharmacol 24:849–850

    PubMed  CAS  Google Scholar 

  • Kaminsky R, Moriarty TM, Bodine J, Wolf DE, Davidson M (1990) Effect of famotidine on deficit symptoms of schizophrenia. Lancet 335:1351–1352

    Article  PubMed  CAS  Google Scholar 

  • Kanba S, Richelson E (1983) Antidepressants are weak competitive antagonists of histamine H2 receptors in dissociated brain tissue. Eur J Pharmacol 94:313–318

    Article  PubMed  CAS  Google Scholar 

  • Kanof PD, Greengard P (1978) Brain histamine receptors as targets for antidepressant drugs. Nature 272:329–333

    Article  PubMed  CAS  Google Scholar 

  • Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KLH, Edwards DD, Shoichet BK, Roth BL (2009) Predicting new molecular targets for known drugs. Nature 462:175–182

    Article  PubMed  CAS  Google Scholar 

  • Kelley MT, Bürckstümmer T, Wenzel-Seifert K, Dove S, Buschauer A, Seifert R (2001) Distinct interaction of human and guinea pig histamine H2 receptor with guanidine-type agonists. Mol Pharmacol 60:1210–1225

    PubMed  CAS  Google Scholar 

  • Kenakin T (2011) Functional selectivity and biased receptor signalling. J Pharmacol Exp Ther 36:296–302

    Article  CAS  Google Scholar 

  • Kleemann P, Papa D, Vigil-Cruz S, Seifert R (2008) Functional reconstitution of the human chemokine receptor CXCR4 with Gi/Go-proteins in Sf9 insect cells. Naunyn-Schmiedeberg’s Arch Pharmacol 378:261–274

    Article  CAS  Google Scholar 

  • Kobilka BK, Deupi X (2007) Conformaional complexity of G-protein-coupled receptors. Trends Pharmacol Sci 28:397–406

    Article  PubMed  CAS  Google Scholar 

  • Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003) H1-histamine receptor affinity predicts short-term weight gain for typicaland atypical antipsychotic drugs. Neuropsychopharmacology 28:519–526

    Article  PubMed  CAS  Google Scholar 

  • Lahdelma L, Oja S, Korhonen M, Andersson LC (2010) Clozapine is cytotoxic to primary cultures of human bone marrow mesenchymal stromal cells. J Clin Psychopharmacol 30:461–463

    Article  PubMed  Google Scholar 

  • Leurs R, Vischer HF, Wijtmans M, de Esch IJ (2011) En route to new blockbuster anti-histamines: surveying the offspring of the expanding histamine receptor family. Trends Pharmacol Sci 32:250–257

    Article  PubMed  CAS  Google Scholar 

  • Lexi-comp (2010) http://www.lexi.com/

  • Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R (2005) Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4-receptor. Identification of 4-methylhistamine as the first potent and selective H4-receptor agonist. J Pharmacol Exp Ther 314:1310–1321

    Article  PubMed  CAS  Google Scholar 

  • Lim HD, Jongejan A, Bakker RA, Haaksma E, de Esch IJP, Leurs R (2008) Phenylalanine 169 in the second extracellular loop of the human histamine H4 receptor is responsible for the difference in agonist binding between human and mouse H4 receptors. J Pharmacol Exp Ther 327:88–96

    Article  PubMed  CAS  Google Scholar 

  • Lim HD, de Graaf C, Jiang W, Sadek P, McGovern PM, Istyastono EP, Bakker RA, de Esch IJ, Thurmond RL, Leurs R (2010) Molecular determinants of ligand binding to H4R species variants. Mol Pharmacol 77:734–743

    Article  PubMed  CAS  Google Scholar 

  • Liu C, Wilson SJ, Kuei C, Lovenberg TW (2001) Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J Pharmacol Exp Ther 299:121–130

    PubMed  CAS  Google Scholar 

  • Marcu EL, Clarfield AM, Kleinman Y, Bits H, Darmon D, Da’as N (2002) Agranulocytosis associated with initiation of famotidine therapy. Ann Pharmacother 36:267–271

    Article  Google Scholar 

  • Moya-Garcia AA, Rodriguez CE, Morilla I, Sanchez-Jimenez F, Ranea JA (2011) The function of histamine receptor H4R in the brain revealed by interaction partners. Front Biosci 3:1058–1066

    Article  Google Scholar 

  • Nath C, Gulati A, Dhawan KN, Gupta GP (1988) Role of central histaminergic mechanism in behavioural depression (swimming despair) in mice. Life Sci 42:2413–2417

    Article  PubMed  CAS  Google Scholar 

  • Nonaka T, Mio M, Doi M, Tasaka K (1992) Histamine-induced differentiation of HL-60 cells. The role of protein kinase A. Biochem Pharmacol 44:1115–1121

    Article  PubMed  CAS  Google Scholar 

  • Nooijen PMM, Carvalho F, Flanagan RJ (2011) Haematological toxicity of clozapine and some other drugs used in psychiatry. Hum Psychopharmacol Clin Exp 26:112–119

    Article  CAS  Google Scholar 

  • Ohta K, Kayashi H, Mizuguchi H, Kagamiyama H, Fujimoto K, Fukui H (1994) Site-directed mutagenesis of the histamine H1 receptor: roles of aspartatic acid107, asparagine108 and threonine194. Biochem Biophys Res Commun 203:1096–1101

    Article  PubMed  CAS  Google Scholar 

  • Olesen OV, Thomsen K, Jensen PN, Wulff CH, Rasmussen NA, Refshammer C, Sørensen J, Bysted M, Christensen J, Rosenberg R (1995) Clozapine serum levels and side effects during steady-state treatment of schizophrenic patients: a cross-sectional study. Psychopharmacology (Berl) 117:371–378

    Article  CAS  Google Scholar 

  • Orange PR, Heath PR, Wright SR, Ramchand CN, Kolkeiwicz L, Pearson RC (1996) Individuals with schizophrenia have an increased incidence of the H2R649G allele for the histamine H2 receptor gene. Mol Psychiatry 1:466–469

    PubMed  CAS  Google Scholar 

  • Oyewumi LK, Vollick D, Merskey H, Plumb C (1994) Famotidine as an adjunct treatment of resistant schizophrenia. J Psychiatry Neurosci 19:145–150

    PubMed  CAS  Google Scholar 

  • Pereira A, Dean B (2006) Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells. Biochem Pharmacol 72:783–793

    Article  PubMed  CAS  Google Scholar 

  • Pertz HH, Görnemann T, Schurad B, Seifert R, Straßer A (2006) Striking differences of action of lisuride stereoisomers at histamine H1 receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 374:215–222

    Article  CAS  Google Scholar 

  • Pierce JR Jr (1983) Cimetidine-associated depression and loss of libido in a woman. Am J Med Sci 286:31–34

    Article  PubMed  Google Scholar 

  • Preuss H, Ghorai P, Kraus A, Dove S, Buschauer A, Seifert R (2007) Constitutive activity and ligand selectivity of human, guinea pig, rat, and canine histamine H2 receptors. J Pharmacol Exp Ther 321:983–995

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007) Crystal structure of the human β2-adrenergic G protein-coupled receptor. Nature 450:383–387

    Article  PubMed  CAS  Google Scholar 

  • Richelson E (1982) Pharmacology of antidepressants in use in the United States. J Clin Psychiatry 43:4–13

    Google Scholar 

  • Ries RK, Gilbert DA, Katon W (1984) Tricyclic antidepressant therapy for peptic ulcer disease. Arch Intern Med 144:566–569

    Article  PubMed  CAS  Google Scholar 

  • Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007) GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318:1266–1273

    Article  PubMed  CAS  Google Scholar 

  • Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N, Choe HW, Hofmann KP, Ernst OP (2008) Crystal structure of opsin in its G-protein-interacting conformation. Nature 455:497–503

    Article  PubMed  CAS  Google Scholar 

  • Schild HO (1947) pA, a new scale for the measurement of drug antagonism. Br J Pharmacol Chemother 2:189–206

    PubMed  CAS  Google Scholar 

  • Schneider EH, Seifert R (2009) Histamine H4 receptor-RGS fusion proteins expressed in Sf9 cells: a sensitive and reliable approach for the functional characterization of histamine H4 receptor ligands. Biochem Pharmacol 78:607–616

    Article  PubMed  CAS  Google Scholar 

  • Schneider EH, Seifert R (2010a) Sf9 cells: a versatile model system to investigate the pharmacological properties of G protein-coupled recetors. Pharmacol Ther 128:387–418

    Article  PubMed  CAS  Google Scholar 

  • Schneider EH, Seifert R (2010b) Coexpression systems as models for the analysis of constitutive GPCR activity. Methods Enzymol 485:527–557

    Article  PubMed  CAS  Google Scholar 

  • Schneider EH, Seifert R (2010c) Fusion proteins as model systems for the analysis of constitutive GPCR activity. Methods Enzymol 485:459–480

    Article  PubMed  CAS  Google Scholar 

  • Schneider EH, Schnell D, Papa D, Seifert R (2009) High constitutive activity and a G protein-independent high-affinity state of the human histamine H4 receptor. Biochemistry 48:1424–1438

    Article  PubMed  CAS  Google Scholar 

  • Schneider EH, Strasser A, Thurmond RL, Seifert R (2010) Structural requirements for inverse agonism and neutral antagonism of indole-, benzimidizole-, and thienopyrrole-derived histamine H4 receptor ligands. J Pharmacol Exp Ther 334:513–521

    Article  PubMed  CAS  Google Scholar 

  • Schnell D, Seifert R (2010) Modulation of histamine H3 receptor function by monovalent ions. Neurosci Lett 472:114–118

    Article  PubMed  CAS  Google Scholar 

  • Schnell D, Burleigh K, Trick J, Seifert R (2010a) No evidence for functional selectivity of proxyfan at the human histamine H3 receptor coupled to defined Gi/Go protein heterotrimers. J Pharmacol Exp Ther 332:996–1005

    Article  PubMed  CAS  Google Scholar 

  • Schnell D, Strasser A, Seifert R (2010b) Comparison of the pharmacological properties of human and rat histamine H3-receptors. Biochem Pharmacol 80:1437–1449

    Article  PubMed  CAS  Google Scholar 

  • Schnell D, Brunskole I, Ladova K, Schneider EH, Igel P, Dove S, Buschauer A, Seifert R (2011) Expression and functional properties of canine, rat, and murine histamine H4 receptors in Sf9 insect cells. Naunyn-Schmiedeberg’s Arch Pharmacol 383:457–470

    Article  CAS  Google Scholar 

  • Schulz M, Schmoldt A (2003) Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58:447–474

    PubMed  CAS  Google Scholar 

  • Schwartz JC, Garbarg M, Quach TT (1981) Histamine receptors in brain as targets for tricyclic antidepressants. Trends Pharmacol Sci 2:122–125

    Article  CAS  Google Scholar 

  • Seifert R (2001) Monovalent anions differentially modulate coupling of the β2-adrenoceptor to G splice variants. J Pharmacol Exp Ther 298:840–847

    PubMed  CAS  Google Scholar 

  • Seifert R, Wenzel-Seifert K (2002) Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 366:381–416

    Article  CAS  Google Scholar 

  • Seifert R, Höer A, Schwaner I, Buschauer A (1992) Histamine increases cytosolic Ca2+ in HL-60 promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and induces functional differentiation. Mol Pharmacol 42:235–241

    PubMed  CAS  Google Scholar 

  • Seifert R, Lee TW, Lam VT, Kobilka BK (1998) Reconstitution of β2-adrenoceptor-GTP-binding-protein interaction in Sf9 cells—high coupling efficiency in a β2-adrenoceptor-G fusion protein. Eur J Biochem 255:369–382

    Article  PubMed  CAS  Google Scholar 

  • Seifert R, Wenzel-Seifert K, Bürckstümmer T, Pertz HH, Schunack W, Dove S, Buschauer A, Elz S (2003) Multiple differences in agonist and antagonist pharmacology between human and guinea pig histamine H1 receptor. J Pharmacol Exp Ther 305:1104–1115

    Article  PubMed  CAS  Google Scholar 

  • Seifert R, Schneider EH, Dove S, Brunskole I, Neumann D, Strasser A, Buschauer A (2011) Pradoxical effects of the “standard” histamine H4-receptor antagonist JNJ7777120: the H4 receptor joins the club of 7 transmembrane domain receptors exhibiting functional selectivity. Mol Pharmacol 79:631–638

    Article  PubMed  CAS  Google Scholar 

  • Selent J, Lopez L, Sanz F, Pastor M (2008) Multi-receptor binding profile of clozapine and olanzapine: a structural study based on the new β2 adrenergic receptor template. Chem Med Chem 3:1194–1198

    PubMed  CAS  Google Scholar 

  • Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S (2011) Structure of the human histamine H1 receptor complex with doxepine. Nature 475:65–70

    Article  PubMed  CAS  Google Scholar 

  • Straßer A, Striegl B, Wittmann HJ, Seifert R (2008) Pharmacological profile of histaprodifens at four recombinant histamine H1 receptor species isoforms. J Pharmacol Exp Ther 324:60–71

    Article  PubMed  CAS  Google Scholar 

  • Straßer A, Wittmann HJ, Kunze M, Elz S, Seifert R (2009) Molecular basis for the selective interaction of syntheticagonists with the human histamine H1-receptor compared with the guinea pig H1-receptor. Mol Pharmacol 75:454–465

    Article  PubMed  CAS  Google Scholar 

  • Sutor S, Heilmann J, Seifert R (2011) Impact of fusion to Giα2 and co-expression with RGS proteins on pharmacological properties of human cannabinoid receptors CB1R and CB2R. J Pharm Pharmacol 63:1043–1055

    Article  PubMed  CAS  Google Scholar 

  • Takino N, Sakurai E, Kuramasu A, Okamura N, Yanai K (2009) Roles of histaminergic neurotransmission on methamphetamine-induced locomotor sensitization and reward: a study of receptors gene knockout mice. Int RevNeurobiol 85:109–116

    Article  CAS  Google Scholar 

  • Thurmond RL, Gelfand EW, Dunford PJ (2008) The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov 7:41–53

    Article  PubMed  CAS  Google Scholar 

  • Tiligada E, Zampeli E, Sander K, Stark H (2009) Histamine H3 and H4 receptors as novel drug targets. Expert Opin Investig Drugs 18:1519–1531

    Article  PubMed  CAS  Google Scholar 

  • Traiffort E, Pollard H, Moreau J, Ruat M, Schwartz JC, Martinez-Mir MI, Palacios JM (1992) Pharmacological characterization and autoradiographic localization of histamine H2 receptors in human brain identified with [125I]iodoaminopotentidine. J Neurochem 59:290–299

    Article  PubMed  CAS  Google Scholar 

  • Wenzel-Seifert K, Seifert R (2000) Molecular analysis of β2-adrenoceptor coupling to Gs-, Gi-, and Gq-proteins. Mol Pharmacol 58:954–966

    PubMed  CAS  Google Scholar 

  • Wieland K, ter Laak AM, Smit MJ, Kühne R, Timmermann H, Leurs R (1999) Mutational analysis of the antagonist-binding site of the histamine H1 receptor. J Biol Chem 274:29994–30000

    Article  PubMed  CAS  Google Scholar 

  • Wilson JA, Boyd EJ, Wormsley KG (1985) Effects of some polycyclic drugs on gastric secretion and on the healing of duodenal ulcers. Acta Psychiatr Scand Suppl 320:93–97

    Article  PubMed  CAS  Google Scholar 

  • Wittmann HJ, Elz S, Seifert R, Strasser A (2011) N α-methylated phenylhistamines exhibit affinity to the hH4R—a pharmacological and molecular modelling study. Naunyn-Schmiedeberg’s Arch Pharmacol 384:287–299

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank G. Wilberg for her competent help with the cell culture. This project was supported by Deutsche Forschungsgemeinschaft Graduate Training Program 760 (R.S.), Deutsche Forschungsgemeinschaft research grant STR 1125/1-1 (A.S.), and the European Union COST program BM0806 (A.S. and R.S.). We also appreciate the most valuable critique and suggestions of the reviewers.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roland Seifert.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Appl, H., Holzammer, T., Dove, S. et al. Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics. Naunyn-Schmiedeberg's Arch Pharmacol 385, 145–170 (2012). https://doi.org/10.1007/s00210-011-0704-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-011-0704-0

Keywords

Navigation