Characterization of Histaminergic Receptors

Marina Strakhova1, Timothy A. Esbenshade1

1 Abbott Laboratories, Abbott Park, Illinois
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 1.19
DOI:  10.1002/0471141755.ph0119s37
Online Posting Date:  June, 2007
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Abstract

This unit describes radioligand binding protocols for histamine H1, H2, H3, and H4 receptors. Because these receptors demonstrate low amino acid sequence homology and divergent pharmacological characteristics, assay conditions vary for each. These protocols can be employed in high‐throughput screening programs aimed at identifying selective agonists and antagonists for these sites.

Keywords: histaminergic receptors; H1 histamine receptors; H2 histamine receptors; H3 histamine receptors; H4 histamine receptors; radioligand binding assays; antihistamines

     
 
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Table of Contents

  • Strategic Planning
  • Basic Protocol 1: Measurement of [3H]Mepyramine Binding to Cloned Human H1 Receptors
  • Alternate Protocol 1: Measurement of [3H]mepyramine Binding to Native H1 Receptors in Tissue Membrane Homogenates
  • Basic Protocol 2: Measurement Of [3H]tiotidine Binding to Cloned Human H2 Receptors
  • Alternate Protocol 2: Measurement of [125I]aminopotentidine Binding to Native H2 Receptors in Tissue Membrane Homogenates
  • Basic Protocol 3: Measurement of [3H]N‐α‐Methyl Histamine Binding to Cloned Human H3 Receptors in Membranes
  • Alternate Protocol 3: Measurement of [3H]N‐α‐Methyl Histamine Binding to Native H3 Receptors
  • Basic Protocol 4: Measurement of [3H]histamine Binding to Cloned Human H4 Receptors in Membranes
  • Support Protocol 1: Data Analysis
  • Reagents and Solutions
  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Measurement of [3H]Mepyramine Binding to Cloned Human H1 Receptors

  Materials
  • Cell line (e.g., HEK‐293 cells; ATCC# CRL‐1573) stably transfected (see De Backer et al., ) with human H 1 receptors using Lipofectamine 2000 (Life Technologies), grown to confluence
  • Cell dissociation buffer (Life Technologies), prewarmed to 37°C
  • Dulbecco's phosphate‐buffered saline (DPBS; calcium‐ and magnesium‐free; see recipe), ice‐cold
  • Na+/K+ assay buffer (see recipe), 25°C
  • 20 µM promethazine (Research Biochemicals) in 50 mM Na+/K+ assay buffer (see recipe), or other unlabeled ligand to measure nonspecific binding (Table 1.19.2)
  • 1.5 nM [3H]mepyramine (20 to 30 Ci/mmol; Perkin‐Elmer Life Sciences; Table 1.19.3) in Na+/K+ assay buffer (see recipe)
  • Test compounds (optional) in Na+/K+ assay buffer (see recipe)
  • 0.5% (v/v) polyethyleneimine (PEI)
  • Rinse buffers (50 mM Tris·Cl; appendix 2A): pH 7.7 at 25°C, pH 7.4 at 0°C
  • Scintillation cocktail: e.g., Microscint 20 (Packard) or Ready‐Solv HP (Beckman Coulter)
  • Tissue homogenizer (e.g., T 25 Ultra‐Turrax; IKA Works)
  • Deep‐well 96‐well microtiter plates (2.2 ml volume; e.g., Bioblocks, Brandel), 2‐ml strip tubes, or 12×75–mm glass test tubes
  • GF/B Unifilter plates (Packard), or equivalent
  • Cell harvester or vacuum filtration manifold (e.g., Packard, Brandel, or Skatron), optional
  • 60°C oven, optional
  • Additional reagents and equipment for performing Bradford, Lowry, or BCA protein assays ( appendix 3A)
    Table 1.9.2   MaterialsAffinity Constants (K i Values) of Reference Agents for the Cloned Human H 1, H 2, H 3, and H 4 ReceptorsProperties of Commercially Available Radioligands for Histamine Receptors

    Compound K i values (nM) Compound source
    H 1 H 2 H 3 H 4
    Agonists
    Histamine 6500 33,000 7.0 8.1 d Sigma
    Imetit 30,000 39,000 0.40 2.7 d RBI
    Immepip 22,000 >100,000 2.8 9.0 d Tocris Cookson
    N‐α‐methyl histamine 10,000 42,000 2.6 23 d RBI
    R‐α‐methyl histamine 57,000 >100,000 2.1 146 d RBI
    S‐α‐methyl histamine >100,000 >100,000 38 RBI
    H 1 Antagonists
    Chlorpheniramine 7.6 6100 1500 RBI
    Diphenhydramine 17 2500 >10,000 >10,000 d RBI
    Promethazine 5.0 200 >10,000 RBI
    H 2 Antagonists
    Burimamide >100,000 2,600 5.1 180 d Smith‐Kline Beecham c
    Cimetidine >10,000 320 >100,000 >10,000 d RBI
    Ranitidine >10,000 77 21,000 >10,000 d RBI
    Tiotidine >100,000 27 30,000 Tocris Cookson
    Zolantidine 1200 41 1700 Tocris Cookson
    H 3 Antagonists
    Ciproxifan 45,000 80,000 0.75 1880 Bioprojet c
    Clobenpropit 2900 5000 0.84 12.8 d RBI
    Iodophenpropit 800 1100 0.72 Tocris Cookson
    Thioperamide >100,000 >100,000 72.6 27 d Tocris Cookson
    A‐331440 2940 14,400 3.2 >10,000 Sigma
    ABT‐239 1620 6760 0.45 >10,000 Abbott Labs c
    H 4 Antagonists
    Thioperamide >100,000 >100,000 72.6 27 d Tocris Cookson
    JNJ7777140 c >10,000 d >1000 d >5000 d 4.1 d Johnson & Johnson
    Radioligand Agonist or antagonist K d for receptor (nM) Specific activity (Ci/mmol) Nonspecific binding Signal‐to‐noise ratio Source Comments
    H 1 Receptor
    [3H]Mepyramine Antagonist 0.5 ‐ 2.0 20‐30 Low High Perkin‐Elmer
    H 2 Receptor
    [3H]Cimetidine Antagonist 100‐500 10‐30 High Low Amersham
    [3H]Tiotidine Antagonist 2‐10 70‐90 High Low Perkin‐Elmer Good SNR for recombinant receptors
    [125I]Iodo‐aminopotentidine Antagonist 0.1‐0.5 2000 High Low Amersham Cost‐limiting for broad‐based screening Custom synthesis required
    H 3 Receptor
    [3H]Histamine Agonist 2‐10 25‐30 High Low Perkin‐Elmer Selectivity: H 3 > H 4 > H 1 > H 2
    [3H]R‐α‐methyl histamine Agonist 0.2‐0.8 20‐50 Moderate Moderate Amersham
    [3H]N‐α‐methyl histamine Agonist 0.2‐0.8 45‐90 Low High Perkin‐Elmer SNR in tissue‐based assays > RαMH
    [125I]Iodo‐proxyfan Antagonist 0.2‐0.5 2000 High Low Amersham Binds to H 3R and sites displaced by metyrapone
    H 4 Receptor
    [3H]Histamine Agonist 50‐200 25‐30 High Low Perkin‐Elmer Selectivity: H 3 > H 4 > H 1 > H 2

     cNot available commercially.
     dLiu et al., .
    Table 1.9.3   MaterialsAffinity Constants (K i Values) of Reference Agents for the Cloned Human H 1, H 2, H 3, and H 4 ReceptorsProperties of Commercially Available Radioligands for Histamine Receptors

    Compound K i values (nM) Compound source
    H 1 H 2 H 3 H 4
    Agonists
    Histamine 6500 33,000 7.0 8.1 d Sigma
    Imetit 30,000 39,000 0.40 2.7 d RBI
    Immepip 22,000 >100,000 2.8 9.0 d Tocris Cookson
    N‐α‐methyl histamine 10,000 42,000 2.6 23 d RBI
    R‐α‐methyl histamine 57,000 >100,000 2.1 146 d RBI
    S‐α‐methyl histamine >100,000 >100,000 38 RBI
    H 1 Antagonists
    Chlorpheniramine 7.6 6100 1500 RBI
    Diphenhydramine 17 2500 >10,000 >10,000 d RBI
    Promethazine 5.0 200 >10,000 RBI
    H 2 Antagonists
    Burimamide >100,000 2,600 5.1 180 d Smith‐Kline Beecham c
    Cimetidine >10,000 320 >100,000 >10,000 d RBI
    Ranitidine >10,000 77 21,000 >10,000 d RBI
    Tiotidine >100,000 27 30,000 Tocris Cookson
    Zolantidine 1200 41 1700 Tocris Cookson
    H 3 Antagonists
    Ciproxifan 45,000 80,000 0.75 1880 Bioprojet c
    Clobenpropit 2900 5000 0.84 12.8 d RBI
    Iodophenpropit 800 1100 0.72 Tocris Cookson
    Thioperamide >100,000 >100,000 72.6 27 d Tocris Cookson
    A‐331440 2940 14,400 3.2 >10,000 Sigma
    ABT‐239 1620 6760 0.45 >10,000 Abbott Labs c
    H 4 Antagonists
    Thioperamide >100,000 >100,000 72.6 27 d Tocris Cookson
    JNJ7777140 c >10,000 d >1000 d >5000 d 4.1 d Johnson & Johnson
    Radioligand Agonist or antagonist K d for receptor (nM) Specific activity (Ci/mmol) Nonspecific binding Signal‐to‐noise ratio Source Comments
    H 1 Receptor
    [3H]Mepyramine Antagonist 0.5 ‐ 2.0 20‐30 Low High Perkin‐Elmer
    H 2 Receptor
    [3H]Cimetidine Antagonist 100‐500 10‐30 High Low Amersham
    [3H]Tiotidine Antagonist 2‐10 70‐90 High Low Perkin‐Elmer Good SNR for recombinant receptors
    [125I]Iodo‐aminopotentidine Antagonist 0.1‐0.5 2000 High Low Amersham Cost‐limiting for broad‐based screening Custom synthesis required
    H 3 Receptor
    [3H]Histamine Agonist 2‐10 25‐30 High Low Perkin‐Elmer Selectivity: H 3 > H 4 > H 1 > H 2
    [3H]R‐α‐methyl histamine Agonist 0.2‐0.8 20‐50 Moderate Moderate Amersham
    [3H]N‐α‐methyl histamine Agonist 0.2‐0.8 45‐90 Low High Perkin‐Elmer SNR in tissue‐based assays > RαMH
    [125I]Iodo‐proxyfan Antagonist 0.2‐0.5 2000 High Low Amersham Binds to H 3R and sites displaced by metyrapone
    H 4 Receptor
    [3H]Histamine Agonist 50‐200 25‐30 High Low Perkin‐Elmer Selectivity: H 3 > H 4 > H 1 > H 2

Alternate Protocol 1: Measurement of [3H]mepyramine Binding to Native H1 Receptors in Tissue Membrane Homogenates

  • Male Hartley strain guinea pigs, 6 to 8 months in age
  • 0.9% NaCl solution in squeeze bottle
  • Dissection instruments (e.g., Stoelting)
    • Small animal decapitator
    • Operating scissors
    • Bone rongeurs
    • Strong forceps
    • Cold dissecting plate (or ice‐filled Petri dish)
    • Scalpel
    • Dissecting knife
  • Gas cylinder containing 60% CO 2/40% O 2 connected to a suitable chamber for anesthetizing guinea pig

Basic Protocol 2: Measurement Of [3H]tiotidine Binding to Cloned Human H2 Receptors

  Materials
  • Na+/K+ assay buffer (see recipe), ice‐cold
  • 1 mM cimetidine (Research Biochemicals) in 50 mM Na+/K+ assay buffer, or other unlabeled ligand to measure nonspecific binding (Table 1.19.2)
  • 0.75 nM [3H]tiotidine (70 to 90 Ci/mmol; Perkin‐Elmer Life Sciences; Table 1.19.3) in 50 mM Na+/K+ assay buffer (see recipe)
  • Test compounds (optional) in Na+/K+ assay buffer (see recipe)
  • 0.5% (v/v) polyethyleneimine (PEI)
  • Rinse buffer, ice‐cold: 50 mM Tris·Cl ( appendix 2A), pH 7.7 at 25°C, pH 7.4 at 0°C
  • Scintillation fluid: Microscint 20 (Packard) or Ready‐Solv HP (Beckman Coulter)
  • Deep well 96‐well microtiter plates (2.2‐ml volume; e.g., Bioblocks, Brandel), 2‐ml strip tubes, or 12×75–mm glass test tubes
  • GF/B filters or Unifilter GF/B plates (Packard), or equivalent
  • Cell harvester or vacuum filtration manifold (e.g., Packard, Brandel, or Skatron), optional
  • 60°C oven, optional
  • Additional reagents and equipment for preparing membranes (see protocol 1) and performing Bradford, Lowry, or BCA protein assays ( appendix 3A)

Alternate Protocol 2: Measurement of [125I]aminopotentidine Binding to Native H2 Receptors in Tissue Membrane Homogenates

  • Male Hartley strain guinea pigs, 6 to 8 months in age
  • 0.9% NaCl solution in squeeze bottle
  • 500 µM cimetidine (Research Biochemicals) in 50 mM Na+/K+ assay buffer, or other unlabeled ligand to measure nonspecific binding (Table 1.19.2)
  • 60 pM [125I]iodoaminopotentidine (2000 Ci/mmol; Amersham; Table 1.19.3) in 50 mM Na+/K+ assay buffer
  • Dissection instruments (e.g., Stoelting)
    • Small animal decapitator
    • Operating scissors
    • Bone rongeurs
    • Strong forceps
    • Cold dissecting plate (or ice‐filled Petri dish)
    • Scalpel
    • Dissecting knife
  • Gas cylinder containing 60% CO 2/40% O 2 connected to a suitable chamber for anesthetizing guinea pig
  • Additional reagents and equipment for preparing guinea pig cortical membranes ( protocol 2)

Basic Protocol 3: Measurement of [3H]N‐α‐Methyl Histamine Binding to Cloned Human H3 Receptors in Membranes

  Materials
  • Cell line (e.g., HEK‐293 cells, ATCC #CRL‐1573, or rat C6 glioma, ATCC #CCL‐107) transfected (see Lovenberg et al., ) with human H 3 receptors, grown to confluence
  • TEP assay buffer (see recipe)
  • Tris/EDTA assay buffer (without proteases; see recipe), ice‐cold
  • 100 µM histamine (Research Biochemicals) in Tris/EDTA assay buffer, or other unlabeled ligand (e.g., 30 µM thioperamide; Tocris Cookson) to measure nonspecific binding (Table 1.19.2)
  • 1 nM [3H]N‐α‐methyl histamine (NAMH; 45 to 90 Ci/mmol; Perkin‐Elmer Life Sciences; Table 1.19.3) in Tris/EDTA assay buffer (see recipe)
  • Test compounds (optional) in Tris/EDTA assay buffer (see recipe)
  • 0.5% (v/v) polyethyleneimine (PEI)
  • Rinse buffer, ice‐cold: 50 mM Tris·Cl ( appendix 2A), pH 7.7 at 25°C, pH 7.4 at 0°C
  • Scintillation fluid: Microscint 20 (Packard) or Ready‐Solv HP (Beckman Coulter)
  • Tissue homogenizer (e.g., T 25 Ultra‐Turrax; IKA Works)
  • Clinical tabletop centrifuge
  • Deep‐well 96‐well microtiter plates (2.2‐ml volume, e.g., Bioblocks, Brandel), 2‐ml strip tubes, or 12 × 75–mm glass test tubes
  • GF/B filters or Unifilter GF/B plates (Packard)
  • Cell harvester or vacuum filtration manifold (e.g., Packard, Brandel, or Skatron)
  • 60°C oven (optional)
  • Additional reagents and equipment for preparing membranes (see protocol 1 and protocol 2) and for Bradford, Lowry, or BCA protein assays ( appendix 3A)

Alternate Protocol 3: Measurement of [3H]N‐α‐Methyl Histamine Binding to Native H3 Receptors

  • Male Sprague‐Dawley rat (200 to 250 g) or male Hartley guinea pig (6 to 8 months in age)
  • TEP assay buffer (see recipe), ice‐cold
  • Tris‐EDTA assay buffer (see recipe)
  • 30 µM thioperamide (Tocris Cookson) in TEP assay buffer, or other unlabeled ligand to measure nonspecific binding (Table 1.19.2)
  • 1.5 nM [3H]N‐α‐methyl histamine (NAMH; 45 to 90 Ci/mmol; Perkin‐Elmer Life Sciences; Table 1.19.3) in TEP assay buffer
  • Additional reagents and equipment for obtaining brain tissue ( protocol 2)

Basic Protocol 4: Measurement of [3H]histamine Binding to Cloned Human H4 Receptors in Membranes

  Materials
  • Cell lines (e.g., human HEK‐293, ATCC# CRL‐1573; or SK‐N‐MC, ATCC# HTB‐10) transfected (Liu et al., ) with human H 4 receptors, grown to confluence
  • TEP assay buffer (see recipe)
  • Tris‐EDTA assay buffer (see recipe)
  • 200 µM thioperamide (Tocris Cookson) in Tris‐EDTA assay buffer (see recipe) to define nonspecific binding
  • [3H]histamine (Perkin‐Elmer)
  • Test compounds
  • Scintillation cocktail: e.g., Ready‐Solv HP (Beckman Coulter)
  • Tissue homogenizer (e.g., T 25 Ultra‐Turrax; IKA Works)
  • Deep‐well 96‐well microtiter plates (2.2 ml volume; e.g., Bioblocks, Brandel), 2‐ml strip tubes, or 12×75–mm glass test tubes
  • GF/B Unifilter plates (Packard), or equivalent
  • Cell harvester or vacuum filtration manifold (e.g., Packard, Brandel, or Skatron), optional
  • 60°C oven, optional
  • Additional reagents and equipment for preparing H 4 receptor membranes (see protocol 1)
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Figures

Videos

Literature Cited

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   Arrang, J.M., Garbarg, M., and Schwartz, J.C. 1983. Autoinhibition of brain histamine release by a novel class (H3) of histamine receptor. Nature 302:832‐837.
   Bakker, R.A., Timmerman, H., and Leurs, R. Histamine receptors: Specific ligands, receptor biochemistry, and signal transduction. 2002. Clin. Allergy Immunol. 17:27‐64.
   Barger, G., and Dale, J.J. 1910. Chemical structure and sympathomimetic action of amines. J. Physiol. 41:19‐59.
   Black, J.W., Duncan, W.A.M., Durant, G.J., Ganellin, C.R., and Parsons, M.E. 1972. Definition and antagonism of histamine H2 receptors. Nature 236:385‐390.
   Brown, J.D., O'Shaughnessy, C.T., Kilpatrick, G.J., Scopes, D.I.C., Beswick, P., Clitherow, J.W., and Barnes, J.C. 1996. Characterization of the specific binding of the histamine H3 receptor antagonist radioligand [3H]GR168320. Eur. J. Pharmacol. 311:305‐310.
   Cheng, Y.C. and Prusoff, W.H. 1973. Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22:3099‐3108.
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   De Backer, M.D., Gommeren, W., Moereels, H., Nobels, G., Van Gompel, P., Leysen, J.E., and Luyten, W.H. 1993. Genomic cloning, heterologous expression and pharmacological characterization of a human histamine H1 receptor. Biochem. Biophys. Res. Commun. 197:1601‐1608.
   de Esch, I.J., Thurmond, R.L., Jongejan, A., and Leurs, R. 2005. The histamine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol. Sci. 26:462‐469.
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   Du Buske, L.M. 1996. Clinical comparison of histamine H1‐receptor antagonist drugs. J. Allergy Clin. Immunol. 98:S307‐S318.
   Esbenshade, T.A., Fox, G.B., and Cowart, M.D. 2006. Histamine H3 receptor antagonists: Preclinical promise for treating obesity and cognitive disorders. Mol. Interv. 6:77‐88.
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   Gantz, I., Munzert, G., Tashiro, T., Schaffer, M., Wang, L., DelValle, J., and Yamada, T. 1991. Molecular cloning of the human histamine H2 receptor. Biochem. Biophys. Res. Commun. 178:1386‐1392.
   Hancock, A.A., Esbenshade, T.A., Krueger, K.M., and Yao, B.B. 2003. Genetic and pharmacological aspects of histamine H3 receptor heterogeneity. J. Life Sci. 73:3043‐3072.
   Harper, E.A., Shankley, N.P., and Black, J.W. 1997. Characterisation of the binding of the histamine H3‐receptor antagonist, [3H]clobenpropit, to sites in guinea‐pig cerebral cortex membranes. Br. J. Pharmacol. 122:432P.
   Hill, S.J., Ganellin, C.R., Timmerman, H., Schwartz, J.C., Shankley, N.P., Young, J.M., Schunack, W., Levi, R., and Haas, H.L. 1997. International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol. Rev. 49:253‐278.
   Jansen, F.P., Rademaker, B., Bast, A., and Timmerman, H. 1992. The first radiolabeled histamine H3 receptor antagonist, [125I]iodophenpropit: Saturable and reversible binding to rat cortex membranes. Eur. J. Pharmacol. 217:203‐205.
   Leurs, R., Smit, M.J., and Timmerman, H. 1995. Molecular pharmacological aspects of histamine receptors. Pharmacol. Ther. 66:413‐463.
   Leurs, R., Bakker, R.A., Timmerman, H., and de Esch, I.J. 2005. The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat. Rev. Drug Discov. 4:107‐120.
   Ligneau, X., Garbarg, M., Vizuete, L., Diaz, J., Purand, K., Stark, H., Schunack, W., and Schwartz, J‐C. 1994. [125I]Iodoproxyfan, a new antagonist to label and visualize cerebral histamine H2 receptors. J. Pharmacol. Exp. Ther. 271:452‐459.
   Liu, C., Ma, X., Jiang, X., Wilson, S.J., Hofstra, C.L., Blevitt, J., Pyati, J., Li, X., Chai, W., Carruthers, N., and Lovenberg, T.W. 2001a. Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol. Pharmacol. 59:420‐426.
   Liu, C., Wilson, S.J., Kuei, C., and Lovenberg, T.W. 2001b. Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J. Pharmacol. Exp. Ther. 299:121‐130.
   Lovenberg, T.W., Roland, B.L., Wilson, S.J., Jiang, X., Pyati, J., Huvar, A., Jackson, M.R., and Erlander, M.G. 1999. Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55:1101‐1107.
   Lovenberg, T.W., Pyati, J., Chang, H., Wilson, S.J., and Erlander, M.G. 2000. Cloning of rat H3 receptor reveals distinct species pharmacological profiles. J. Pharmacol. Exp. Therap. 293:771‐778.
   Oda, T., Morikawa, N., Saito, Y., Masuho, Y., and Matsumoto, S.‐I. 2000. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J. Biol. Chem. 275:36781‐36786.
   Thurmond, R.L., Desai, P.J., Dunford, P.J., Fung‐Leung, W.‐P., Hofstra, C.L., Jiang, W., Nguyen, S., Riley, J.P., Sun, S., Williams, K.N., Edwards, J.P., and Karlsson, L. 2004. A potent and selective histamine H4 receptor sntagonist with snti‐Inflammatory properties. J. Pharmacol. Exp. Ther. 309:404‐413.
   West, R.E. Jr., Zwieg, A., Shih, N.Y., Siegel, M.I., Egan, R.W., and Clark, M.A. 1990. Identification of H3 histamine receptor subtypes. Mol. Pharmacol. 38:610‐613.
   West, R.E. Jr., Wu, R‐L., Billah, M.M., Egan, R.W., and Anthes, J.C. 1999. The profiles of human and primate [3H]Nα‐methyl histamine binding differ from that of rodents. Eur. J. Pharmacol. 177:233‐239.
   Witte, D.G., Yao, B.B., Miller, T.R., Carr, T.L., Cassar, S., Sharma, R., Faghih, R., Surber, B.W., Esbenshade, T.A., Hancock, A.A., and Krueger, K.M. 2006. Detection of multiple H3 receptor affinity states utilizing [3H]A‐349821, a novel, selective, non‐imidazole histamine H3 receptor inverse agonist radioligand. Br. J. Pharmacol. 148:657‐670.
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Key References
   De Backer, et al., 1993. See above.
  Cloning of the human H1 receptor gene and initial pharmacological characterization.
   Gantz et al., 1991. See above.
  Cloning of the human H2 receptor gene and initial pharmacological characterization.
   Gajtkowski, G.A., Norris, D.B., Rising, T.J., and Wood, T.P. 1983. Specific binding of [3H]tiotidine to histamine H2 receptors in guinea‐pig cerebral cortex. Nature 304:65‐67.
  First successful radioligand described for H2 receptors after a number of false starts.
   Hancock et al., 2003. See above.
  Comprehensive review of histamine H3 receptor isoform heterogeneity.
   Lovenberg et al., 1999. See above.
  Cloning of the human H3 receptor gene and initial pharmacological characterization.
   Oda et al., 2000. See above.
  Cloning of the human H4 receptor gene and initial pharmacological characterization.
   West et al., 1999. See above.
  Characterization of homogenate radioligand binding in rat, human and non‐human primate brain indicating pharmacological differences may exist.
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