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The histamine H3 receptor: from gene cloning to H3 receptor drugs

Nature Reviews Drug Discovery volume 4, pages 107–120 (2005)Cite this article

Key Points

  • The therapeutic modulation of several actions of the biogenic amine histamine has proved to be medically effective and also financially profitable. Antagonists that target the histamine H1 receptor (H1R) or the H2 receptor, which are used in the treatment of allergic conditions and gastric-acid-related disorders, respectively, have been 'blockbuster' drugs for many years.

  • Following the Human Genome Project, the family of histamine receptors has been extended to include four different G-protein-coupled receptors (GPCRs): the H1, H2, H3 and H4 receptors, and current expectations for the therapeutic potential of drugs that target the H3 and/or H4 receptor are high.

  • The identification of the H3 receptor at the molecular level in 1999 has greatly facilitated drug discovery efforts to target the H3 receptor, and currently many pharmaceutical companies are active in this field.

  • As reviewed in this article, many potent and relatively selective H3 receptor agonists and inverse agonists have now been developed. For both H3 receptor agonists and H3 receptor inverse agonists/antagonists, interesting activities in several preclinical models of important human diseases, including obesity, migraine, attention-deficit hyperactivity disorder, and inflammatory diseases, have been reported.

Abstract

Since the cloning of the histamine H3 receptor cDNA in 1999 by Lovenberg and co-workers, this histamine receptor has gained the interest of many pharmaceutical companies as a potential drug target for the treatment of various important disorders, including obesity, attention-deficit hyperactivity disorder, Alzheimer's disease, schizophrenia, as well as for myocardial ischaemia, migraine and inflammatory diseases. Here, we discuss relevant information on this target protein and describe the development of various H3 receptor agonists and antagonists, and their effects in preclinical animal models.

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Figure 1: H3-receptor activation can result in the modulation of diverse signalling pathways.
Figure 2: Imidazole-containing histamine H3 receptor agonists.
Figure 3
Figure 4

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References

  1. Ma, P. & Zemmel, R. Value of novelty? Nature Rev. Drug Discov., 1, 571–572 (2002).

    CAS  Google Scholar 

  2. Hough, L. B. Genomics meets histamine receptors: new subtypes, new receptors. Mol. Pharmacol. 59, 415–419 (2001).

    CAS  PubMed  Google Scholar 

  3. Arrang, J. M., Garbarg, M. & Schwartz, J. C. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302, 832–837 (1983). The first description of the histamine H 3 receptor in rat brain on the basis of pharmacological data.

    CAS  PubMed  Google Scholar 

  4. Haas, H. & Panula, P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nature Rev. Neurosci. 4, 121–130 (2003). Timely review on the role of histamine in the brain.

    CAS  Google Scholar 

  5. Lovenberg, T. W. et al. Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55, 1101–1107 (1999). First identification of the H 3 receptor as a G-protein coupled receptor.

    CAS  PubMed  Google Scholar 

  6. Drutel, G. et al. Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol. Pharmacol. 59, 1–8 (2001). Description of H 3 receptor isoforms with different localization and signal transduction efficiencies.

    CAS  PubMed  Google Scholar 

  7. Héron, A. et al. Expression analysis of the histamine H3 receptor in developing rat tissues. Mech. Dev. 105, 167–173 (2001).

    PubMed  Google Scholar 

  8. Pollard, H. et al. A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 52, 169–189 (1993).

    CAS  PubMed  Google Scholar 

  9. Chazot, P. L. et al. Immunological identification of the mammalian H3 histamine receptor in the mouse brain. Neuroreport 12, 259–262 (2001).

    CAS  PubMed  Google Scholar 

  10. Leurs, R. et al. H3 receptor gene is cloned at last. Trends Pharmacol. Sci. 21, 11–12 (2000).

    CAS  PubMed  Google Scholar 

  11. Gantz, I. et al. Molecular cloning of a gene encoding the histamine H2 receptor. Proc. Natl Acad. Sci. USA 88, 429–433 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Yamashita, M. et al. Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc. Natl Acad. Sci. USA 88, 11515–11519 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Oda, T. et al. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J. Biol. Chem. 275, 36781–36786 (2000). Identification of the histamine H 4 receptor, which shows high similarity to the H 3 receptor. Many classical H 3 receptor ligands also bind to the H 4 receptor.

    CAS  PubMed  Google Scholar 

  14. Nakamura, T. et al. Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem. Biophys. Res. Commun. 279, 615–620 (2000).

    CAS  PubMed  Google Scholar 

  15. Liu, C. et al. Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol. Pharmacol. 59, 420–426 (2001).

    CAS  PubMed  Google Scholar 

  16. Morse, K. L. et al. Cloning and characterization of a novel human histamine receptor. J. Pharmacol. Exp. Ther. 296, 1058–1066 (2001).

    CAS  PubMed  Google Scholar 

  17. Zhu, Y. et al. Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol. Pharmacol. 59, 434–441 (2001).

    CAS  PubMed  Google Scholar 

  18. Nguyen, T. et al. Discovery of a novel member of the histamine receptor family. Mol. Pharmacol. 59, 427–433 (2001).

    CAS  PubMed  Google Scholar 

  19. Hancock, A. A. et al. Genetic and pharmacological aspects of histamine H3 receptor heterogeneity. Life Sci. 73, 3043–3072 (2003). This paper summarizes available information on H 3 receptor isoforms.

    CAS  PubMed  Google Scholar 

  20. Wiedemann, P. et al. Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations. J. Neural Transm. 109, 443–453 (2002).

    CAS  PubMed  Google Scholar 

  21. Wellendorph, P. et al. Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H3 receptor. Neuropharmacology 42, 929–940 (2002).

    CAS  PubMed  Google Scholar 

  22. Cogé, F. et al. Genomic organization and characterization of splice variants of the human histamine H3 receptor. Biochem. J. 355, 279–288 (2001).

    PubMed  PubMed Central  Google Scholar 

  23. Liu, C., Ma, X. J. & Lovenberg, T. W. Alternative splicing of the histamine H3 receptor mRNA at the third cytoplasmic loop is not detectable in humans. Brain Res. Mol. Brain Res. 83, 145–150 (2000).

    CAS  PubMed  Google Scholar 

  24. Shenton, F. et al. Human H3 receptor isoforms can form homooligomers. XXXIII Ann. Meet. Eur. Histamine Res. Soc. Abs. P104 (2004).

  25. Morisset, S. et al. High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature 408, 860–864 (2000). The H 3 receptor is one of the few GPCRs shown to exert high levels of constitutive signalling in native tissues.

    CAS  PubMed  Google Scholar 

  26. Yao, B. B. et al. Molecular modeling and pharmacological analysis of species-related histamine H3 receptor heterogeneity. Neuropharmacology 44, 773–786 (2003).

    CAS  PubMed  Google Scholar 

  27. Coge, F. et al. Genomic organization and characterization of splice variants of the human histamine H3 receptor. Biochem. J. 355, 279–288 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wulff, B. S., Hastrup, S. & Rimvall, K. Characteristics of recombinantly expressed rat and human histamine H3 receptors. Eur. J. Pharmacol. 453, 33–41 (2002).

    CAS  PubMed  Google Scholar 

  29. Morisset, S. et al. The rat H3 receptor: gene organization and multiple isoforms. Biochem. Biophys. Res. Commun. 280, 75–80 (2001).

    CAS  PubMed  Google Scholar 

  30. Lovenberg, T. W. et al. Cloning of rat histamine H3 receptor reveals distinct species pharmacological profiles. J. Pharmacol. Exp. Ther. 293, 771–778 (2000).

    CAS  PubMed  Google Scholar 

  31. Tardivel-Lacombe, J. et al. Cloning and cerebral expression of the guinea pig histamine H3 receptor: evidence for two isoforms. Neuroreport 11, 755–759 (2000).

    CAS  PubMed  Google Scholar 

  32. Cassar, S. Cloning of the guinea pig H3 receptor. Neuroreport 11, L3–L4 (2000).

    CAS  PubMed  Google Scholar 

  33. Chen, J., Liu, C. & Lovenberg, T. W. Molecular and pharmacological characterization of the mouse histamine H3 receptor. Eur. J. Pharmacol. 467, 57–65 (2003).

    CAS  PubMed  Google Scholar 

  34. Yao, B. B. et al. Cloning and pharmacological characterization of the monkey histamine H3 receptor. Eur. J. Pharmacol. 482, 49–60 (2003).

    CAS  PubMed  Google Scholar 

  35. Ireland-Denny, L. et al. Species-related pharmacological heterogeneity of histamine H3 receptors. Eur. J. Pharmacol. 433, 141–150 (2001).

    CAS  PubMed  Google Scholar 

  36. Tardivel-Lacombe, J. et al. Chromosomal mapping and organization of the human histamine H3 receptor gene. Neuroreport 12, 321–324 (2001).

    CAS  PubMed  Google Scholar 

  37. Rouleau, A. et al. Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms. J. Neurochem. 90, 1331–1338 (2004).

    CAS  PubMed  Google Scholar 

  38. Toyota, H. et al. Behavioral characterization of mice lacking histamine H3 receptors. Mol. Pharmacol. 62, 389–397 (2002).

    CAS  PubMed  Google Scholar 

  39. Takahashi, K. et al. Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype. J. Clin. Invest. 110, 1791–1799 (2002). References 38 and 39 report initial results with H 3 receptor knockout mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Chazot, P. L. & Shenton, F. C. H3 Histamine receptors: the gene knockout data so far. Curr. Anaesth. Crit. Care 15, 23–28 (2004).

    Google Scholar 

  41. Clark, E. A. & Hill, S. J. Sensitivity of histamine H3 receptor agonist-stimulated [35S]GTP?S binding to pertussis toxin. Eur. J. Pharmacol. 296, 223–225 (1996).

    CAS  PubMed  Google Scholar 

  42. Giovannini, M. G. et al. Improvement in fear memory by histamine-elicited ERK2 activation in hippocampal CA3 cells. J. Neurosci. 23, 9016–9023 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Rouleau, A. et al. Histamine H3-receptor-mediated [35S]GTPγS binding: evidence for constitutive activity of the recombinant and native rat and human H3 receptors. Br. J. Pharmacol. 135, 383–392 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Silver, R. B. et al. Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: a novel protective mechanism in myocardial ischemia. Proc. Natl Acad. Sci. USA 98, 2855–2859 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Silver, R. B. et al. Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of noradrenaline exocytosis from cardiac sympathetic nerve endings. Proc. Natl Acad. Sci. USA 99, 501–506 (2002).

    CAS  PubMed  Google Scholar 

  46. Molina-Hernandez, A. et al. Histamine H3 receptor activation inhibits glutamate release from rat striatal synaptosomes. Neuropharmacology 41, 928–934 (2001).

    CAS  PubMed  Google Scholar 

  47. Bongers, G. et al. Modulation of Akt/GSK3-β axis as new signaling properties of the histamine H3 receptor. XXXIII Ann. Meet. Eur. Histamine Res. Soc. Abs. P25 (2004).

  48. Sun, W. et al. Glycogen synthase kinase-3β is complexed with tau protein in brain microtubules. J. Biol. Chem. 277, 11933–11940 (2002).

    CAS  PubMed  Google Scholar 

  49. Lin, C. H. et al. A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31, 841–851 (2001).

    CAS  PubMed  Google Scholar 

  50. Gomez-Ramirez, J., Ortiz, J. & Blanco, I. Presynaptic H3 autoreceptors modulate histamine synthesis through cAMP pathway. Mol. Pharmacol. 61, 239–245 (2002).

    CAS  PubMed  Google Scholar 

  51. Jope, R. S. & Johnson, G. V. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29, 95–102 (2004).

    CAS  PubMed  Google Scholar 

  52. Leurs, R., Vollinga, R. C. & Timmerman, H. The medicinal chemistry and therapeutic potentials of ligands of the histamine H3 receptor. Prog. Drug Res. 45, 107–165 (1995).

    CAS  PubMed  Google Scholar 

  53. De Esch, I. J. & Belzar, K. L. Histamine H3 receptor agonists. Mini Rev. Med. Chem. 4, 955–963 (2004).

    CAS  PubMed  Google Scholar 

  54. Krause, M., Stark, H. & Schunack, W. in The Histamine H3 Receptor: a Target For New Drugs (eds Leurs R. & Timmerman, H.) 175–196 (Elsevier, Amserdam, 1998).

    Google Scholar 

  55. Arrang, J. M. et al. Highly potent and selective ligands for histamine H3-receptors. Nature 327, 117–123 (1987). This paper described the discovery of ( R )-α-methylhistamine and thioperamide as a first set of relatively selective H 3 receptor ligands.

    CAS  PubMed  Google Scholar 

  56. Krause, M. et al. Synthesis, X-ray crystallography, and pharmacokinetics of novel azomethine prodrugs of (R)-α-methylhistamine: highly potent and selective histamine H3 receptor agonists. J. Med. Chem. 38, 4070–4079 (1995).

    CAS  PubMed  Google Scholar 

  57. Rouleau, A. et al. Bioavailability, antinociceptive and antiinflammatory properties of BP 2-94, a histamine H3 receptor agonist prodrug. J. Pharmacol. Exp. Ther. 281, 1085–1094 (1997). First description of a bioavailable H 3 receptor agonist prodrug with therapeutic potential for peripheral applications.

    CAS  PubMed  Google Scholar 

  58. Garbarg, M. et al. S-[2-(4-imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist. J. Pharmacol. Exp. Ther. 263, 304–310 (1992).

    CAS  PubMed  Google Scholar 

  59. Van der Goot, H. et al. Isothiourea analogues of histamine as potent agonists or antagonists of the histamine H3 receptor. Eur. J. Med. Chem. 27, 511–517 (1992).

    CAS  Google Scholar 

  60. Shih, N. Y. et al. Trans-4-methyl-3-imidazoyl pyrrolidine as a potent, highly selective histamine H3 receptor agonist in vivo. Bioorg. Med. Chem. Lett. 8, 243–248 (1998).

    CAS  PubMed  Google Scholar 

  61. Jansen, F. P. et al. In vivo modulation of rat hypothalamic histamine release by the histamine H3 receptor ligands, immepip and clobenpropit. Effects of intrahypothalamic and peripheral application. Eur. J. Pharmacol. 362, 149–155 (1998).

    CAS  PubMed  Google Scholar 

  62. Coruzzi, G. et al. Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat. Naunyn Schmiedebergs Arch. Pharmacol. 351, 569–575 (1995).

    CAS  PubMed  Google Scholar 

  63. Hey, J. A. et al. (R)-α-methylhistamine augments neural, cholinergic bronchospasm in guinea pigs by histamine H1 receptor activation. Eur. J. Pharmacol. 211, 421–426 (1992).

    CAS  PubMed  Google Scholar 

  64. Vollinga, R. C. et al. A new potent and selective histamine H3 receptor agonist, 4-(1H-imidazol-4-ylmethyl)piperidine. J. Med. Chem. 37, 332–333 (1994).

    CAS  PubMed  Google Scholar 

  65. Kitbunnadaj, R. et al. Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H3 receptor agonist. J. Med. Chem. 47, 2414–2417 (2004).

    CAS  PubMed  Google Scholar 

  66. Kitbunnadaj, R. et al. N-substituted piperidinyl alkyl imidazoles: discovery of methimepip as a potent and selective histamine H3 receptor agonist. J. Med. Chem. 24 Nov 2004 (10.1021/jm049475h). Description of an H 3 receptor agonist with a 2,000-fold selectivity over the H 4 receptor.

  67. Leurs, R. Molecular pharmacology of the histamine H3 receptor. Exper. Biol. 2004. (2004).

  68. Vollinga, R. C. et al. Homologs of histamine as histamine H3 receptor antagonists: a new potent and selective H3 antagonist, 4(5)-(5-aminopentyl)-1H-imidazole. J. Med. Chem. 38, 266–271 (1995).

    CAS  PubMed  Google Scholar 

  69. Wieland, K. et al. Constitutive activity of histamine H3 receptors stably expressed in SK-N-MC cells: display of agonism and inverse agonism by H3 antagonists. J. Pharmacol. Exp. Ther. 299, 908–914 (2001).

    CAS  PubMed  Google Scholar 

  70. Sasse, A. et al. Novel partial agonists for the histamine H3 receptor with high in vitro and in vivo activity. J. Med. Chem. 42, 4269–4274 (1999).

    CAS  PubMed  Google Scholar 

  71. Pelloux-Leon, N. et al. Meta-substituted aryl(thio)ethers as potent partial agonists (or antagonists) for the histamine H3 receptor lacking a nitrogen atom in the side chain. J. Med. Chem. 47, 3264–3274 (2004).

    CAS  PubMed  Google Scholar 

  72. Lin, J. S. Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons. Sleep Med. Rev. 4, 471–503 (2000). Review describing the role of histamine and the H 3 receptor in the regulation of sleep-wakefulness.

    CAS  PubMed  Google Scholar 

  73. Welch, M. J., Meltzer, E. O. & Simons, F. E. H1-antihistamines and the central nervous system. Clin. Allergy Immunol. 17, 337–388 (2002).

    CAS  PubMed  Google Scholar 

  74. McLeod, R. L. et al. Sch 50971, an orally active histamine H3 receptor agonist, inhibits central neurogenic vascular inflammation and produces sedation in the guinea pig. J. Pharmacol. Exp. Ther. 287, 43–50 (1998).

    CAS  PubMed  Google Scholar 

  75. Cannon, K. E. et al. Activation of spinal histamine H3 receptors inhibits mechanical nociception. Eur. J. Pharmacol. 470, 139–147 (2003).

    CAS  PubMed  Google Scholar 

  76. Levi, R. & Smith, N. C. Histamine H3-receptors: a new frontier in myocardial ischemia. J. Pharmacol. Exp. Ther. 292, 825–830 (2000).

    CAS  PubMed  Google Scholar 

  77. Koyama, M., Heerdt, P. M. & Levi, R. Increased severity of reperfusion arrhythmias in mouse hearts lacking histamine H3-receptors. Biochem. Biophys. Res. Commun. 306, 792–796 (2003).

    CAS  PubMed  Google Scholar 

  78. Matsubara, T., Moskowitz, M. A. & Huang, Z. UK-14,304, R(-)-α-methyl-histamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanisms. Eur. J. Pharmacol. 224, 145–150 (1992).

    CAS  PubMed  Google Scholar 

  79. Ichinose, M., Belvisi, M. G. & Barnes, P. J. Histamine H3-receptors inhibit neurogenic microvascular leakage in airways. J. Appl. Physiol. 68, 21–25 (1990).

    CAS  PubMed  Google Scholar 

  80. O'Connor, B. J., Lecomte, J. M. & Barnes, P. J. Effect of an inhaled histamine H3-receptor agonist on airway responses to sodium metabisulphite in asthma. Br. J. Clin. Pharmacol. 35, 55–57 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Fozard, J. R. BP-294 Ste Civile Bioprojet. Curr. Opin. Investig. Drugs 1, 86–89 (2000).

    CAS  PubMed  Google Scholar 

  82. Schwartz, J. C. The histamine H3 receptor: from molecular pharmacology to clinical applications. IInd Int. Symp. Mol. Med. Abs. (2002).

  83. Millán-Guerrero, R. O. et al. Nα-methylhistamine safety and efficacy in migraine prophylaxis: phase I and phase II studies. Headache 43, 389–394 (2003).

    PubMed  Google Scholar 

  84. Hancock, A. A. H3 Receptor antagonists/inverse agonists as anti-obesity agents. Curr. Opin. Investig. Drugs 4, 1190–1197 (2003). Review describing the role of histamine and the H 3 receptor in food intake and the therapeutic potential of H 3 receptor antagonists as anti-obesity drugs.

    CAS  PubMed  Google Scholar 

  85. Stark, H. Recent advances in histamine H3/H4 receptor ligands. Expert Opin. Ther. Patents 13, 851–865 (2003). This paper reviews the structure–activity relationships of the various H 3 receptor ligands. Information from the extensive patent literature is included as well in this review.

    CAS  Google Scholar 

  86. Howard, H. R. Agents for attention-deficit hyperactivity disorder an update. Expert Opin. Ther. Patents 14, 983–1008 (2004).

    CAS  Google Scholar 

  87. Arrang, J. M., Garbarg, M. & Schwartz, J. C. Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors. Neuroscience 23, 149–157 (1987).

    CAS  PubMed  Google Scholar 

  88. Esbenshade, T. A. et al. Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects. J. Pharmacol. Exp. Ther. 305, 887–896 (2003).

    CAS  PubMed  Google Scholar 

  89. Gbahou, F. et al. Protean agonism at histamine H3 receptors in vitro and in vivo. Proc. Natl Acad. Sci. USA 100, 11086–11091 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ligneau, X. et al. Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist. J. Pharmacol. Exp. Ther. 287, 658–666 (1998).

    CAS  PubMed  Google Scholar 

  91. Hancock, A. A. et al. Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist. Eur. J. Pharmacol. 487, 183–197 (2004).

    CAS  PubMed  Google Scholar 

  92. Stark, H. et al. [125I]iodoproxyfan and related compounds: a reversible radioligand and novel classes of antagonists with high affinity and selectivity for the histamine H3 receptor. J. Med. Chem. 39, 1220–1226 (1996).

    CAS  PubMed  Google Scholar 

  93. Stark, H. et al. General construction pattern of histamine H3-receptor antagonists: change of a paradigm. Bioorg. Med. Chem. Lett. 8, 2011–2016 (1998).

    CAS  PubMed  Google Scholar 

  94. De Esch, I. J. et al. Synthesis and histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles and 4-(ω-phenylalkyl)-1H-imidazoles. Bioorg. Med. Chem. 7, 3003–3009 (1999).

    CAS  PubMed  Google Scholar 

  95. Ali, S. M. et al. Design, synthesis, and structure–activity relationships of acetylene-based histamine H3 receptor antagonists. J. Med. Chem. 42, 903–909 (1999).

    CAS  PubMed  Google Scholar 

  96. Liu, H. et al. An efficient multigram synthesis of the potent histamine H3 antagonist GT-2331 and the reassessment of the absolute configuration. J. Org. Chem. 69, 192–194 (2004).

    CAS  PubMed  Google Scholar 

  97. Aslanian, R. et al. Identification of a novel, orally bioavailable histamine H3 receptor antagonist based on the 4-benzyl-(1H-imidazol-4-yl) template. Bioorg. Med. Chem. Lett. 12, 937–941 (2002).

    CAS  PubMed  Google Scholar 

  98. De Esch, I. J. et al. Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE. J. Med. Chem. 44, 1666–1674 (2001).

    CAS  PubMed  Google Scholar 

  99. Mills, J. E. et al. SLATE: a method for the superposition of flexible ligands. J. Comput. Aided Mol. Des. 15, 81–96 (2001).

    CAS  PubMed  Google Scholar 

  100. Aslanian, R. et al. Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. Bioorg. Med. Chem. Lett. 13, 1959–1961 (2003).

    CAS  PubMed  Google Scholar 

  101. LaBella, F. S. et al. H3 receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450. Br. J. Pharmacol. 107, 161–164 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Yang, R. et al. Coordination of histamine H3 receptor antagonists with human adrenal cytochrome P450 enzymes. Pharmacology 66, 128–135 (2002).

    CAS  PubMed  Google Scholar 

  103. Ganellin, C. R. et al. Synthesis of potent non-imidazole histamine H3-receptor antagonists. Arch. Pharm. (Weinheim), 331, 395–404 (1998). Systematic modification of lead structures leading to the first non-imidazole H 3 receptor antagonists.

    CAS  Google Scholar 

  104. Menge, W. M. et al. Synthesis and biological evaluation of a novel class of non-imidazole histamine H3 antagonists. 15th EFMC Int. Symp. Med. Chem. (1998).

  105. Meier, G. et al. Piperidino-hydrocarbon compounds as novel non-imidazole histamine H3-receptor antagonists. Bioorg. Med. Chem. 10, 2535–2542 (2002).

    CAS  PubMed  Google Scholar 

  106. Faghih, R. et al. Structure–activity relationships of A-331440: a new histamine-3 antagonist with anti-obesity properties. Inflamm. Res. 53 (Suppl. 1), S79–S80 (2004).

    CAS  PubMed  Google Scholar 

  107. Cowart, M. et al. A new class of potent non-imidazole H3 antagonists: 2-aminoethylbenzofurans. Bioorg. Med. Chem. Lett. 14, 689–693 (2004).

    CAS  PubMed  Google Scholar 

  108. Cowart, M. et al. The medicinal chemistry of novel H3 antagonists. Inflamm. Res. 53 (Suppl. 1), S69–S70 (2004).

    CAS  PubMed  Google Scholar 

  109. Pharmaceutical Research and Manufacturers of America [online], <http://www.phrma.org> (2004).

  110. Cowart, M. et al. Achievement of behavioral efficacy and improved potency in new heterocyclic analogs of benzofuran H3 antagonists. XXXIII Ann. Meet. Eur. Histamine Res. Soc. Abs. P34 (2004).

  111. Apodaca, R. et al. A new class of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy) benzylamines. J. Med. Chem. 46, 3938–3944 (2003).

    CAS  PubMed  Google Scholar 

  112. Carruthers, N. I. (1-[4-(3-Piperidin-1-ylpropoxy)benzyl] piperidine): a template for the design of potent and selective non-imidazole histamine H3 receptor antagonists. XXXIII Ann. Meet. Eur. Histamine Res. Soc. Abs. P31 (2004).

  113. Zaragoza, F. et al. 1-alkyl-4-acylpiperazines as a new class of imidazole-free histamine H3 receptor antagonists. J. Med. Chem. 47, 2833–2838 (2004).

  114. McLeod, R. L. et al. Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). J. Pharmacol. Exp. Ther. 305, 1037–1044 (2003).

    CAS  PubMed  Google Scholar 

  115. Varty, L. M. et al. Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction. Eur. J. Pharmacol. 484, 83–89 (2004).

    CAS  PubMed  Google Scholar 

  116. McLeod, R. L. et al. Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion. Am. J. Rhinol. 13, 391–399 (1999).

    CAS  PubMed  Google Scholar 

  117. Mokdad, A. H. et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289, 76–79 (2003).

    PubMed  Google Scholar 

  118. Sakata, T. & Yoshimatsu, H. Homeostatic maintenance regulated by hypothalamic neuronal histamine. Methods Find. Exp. Clin. Pharmacol. 17 (Suppl. C), 51–56 (1995).

    CAS  PubMed  Google Scholar 

  119. Kroeze, W. K. et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519–526 (2003).

    CAS  PubMed  Google Scholar 

  120. Karlstedt, K. et al. Expression of the H3 receptor in the developing CNS and brown fat suggests novel roles for histamine. Mol. Cell Neurosci. 24, 614–622 (2003).

    CAS  PubMed  Google Scholar 

  121. Mochizuki, T. et al. In vivo release of neuronal histamine in the hypothalamus of rats measured by microdialysis. Naunyn Schmiedebergs Arch. Pharmacol. 343, 190–195 (1991).

    CAS  PubMed  Google Scholar 

  122. Sindelar, D. K. et al. Central H3R activation by thioperamide does not affect energy balance. Pharmacol. Biochem. Behav. 78, 275–283 (2004).

    CAS  PubMed  Google Scholar 

  123. Hancock, A. A. et al. In vitro optimization of structure activity relationships of analogues of A-331440 combining radioligand receptor binding assays and micronucleus assays of potential antiobesity histamine H3 receptor antagonists. Basic Clin. Pharmacol. Toxicol. 95, 144–152 (2004).

    CAS  PubMed  Google Scholar 

  124. Rimvall, K. Effects of novel histamine H3 receptor antagonists on food intake and body weight in rodents and in larger species. Exper. Biol. 2004. (2004).

  125. Kay, G. G. The effects of antihistamines on cognition and performance. J. Allergy Clin. Immunol. 105, S622–S627 (2000).

    CAS  PubMed  Google Scholar 

  126. Tashiro, M. et al. Roles of histamine in regulation of arousal and cognition: functional neuroimaging of histamine H1 receptors in human brain. Life Sci. 72, 409–414 (2002).

    CAS  PubMed  Google Scholar 

  127. Fox, G. B. et al. Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization. J. Pharmacol. Exp. Ther. 305, 897–908 (2003).

    CAS  PubMed  Google Scholar 

  128. Ishizuka, T. et al. Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci. Lett. 339, 143–146 (2003).

    CAS  PubMed  Google Scholar 

  129. Tedford, C. E. et al. Effects of a novel, selective and potent histamine H3 receptor antagonist, GT-2331, on rat sleep-wakefulness and canine cataplexy. Soc. Neurosci. Abstr. 26, 460.3. (2000)

  130. Hancock, A. A. & Fox, G. B. in Milestones in Drug Therapy (ed. Buccafusco, J. J.). (Birkhäuser, Basel, 2003).

    Google Scholar 

  131. Passani, M. B. et al. Central histaminergic system and cognition. Neurosci. Biobehav. Rev. 24, 107–113 (2000).

    CAS  PubMed  Google Scholar 

  132. Mochizuki, T. et al. Histaminergic modulation of hippocampal acetylcholine release in vivo. J. Neurochem. 62, 2275–2282 (1994).

    CAS  PubMed  Google Scholar 

  133. Giovannini, M. G. et al. Effects of histamine H3 receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia. Behav. Brain Res. 104, 147–155 (1999).

    CAS  PubMed  Google Scholar 

  134. Meguro, K. et al. Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice. Pharmacol. Biochem. Behav. 50, 321–325 (1995).

    CAS  PubMed  Google Scholar 

  135. Prast, H., Argyriou, A. & Philippu, A. Histaminergic neurons facilitate social memory in rats. Brain Res. 734, 316–318 (1996).

    CAS  PubMed  Google Scholar 

  136. Fox, G. B. et al. Effects of histamine H3 receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup. Behav. Brain Res. 131, 151–161 (2002).

    CAS  PubMed  Google Scholar 

  137. Fox, G. B. et al. Cognition enhancing effects of novel H3 receptor (H3R) antagonists in several animal models. Inflamm. Res. 53 (Suppl. 1), S49–S50 (2004).

    CAS  PubMed  Google Scholar 

  138. Esbenshade, T. A. et al. ABT-239, a novel, selective, and potent human histamine H3 receptor antagonist with cognition enhancing properties. Exp. Biol. 2004. Abstr. 396.2 (2004).

  139. Medhurst, A. D. & Wilson, D. M. Pre-clinical evaluation of novel H3 receptor antagonists. XXXIII Ann. Meet. Eur. Histamine Res. Soc. Abstr. P83 (2004).

  140. Yates, S. L. et al. Inverse agonists of the histamine-3 receptor as appetite suppressants. Abstr. Amer. Chem. Soc. 255, MEDI2 (2003).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  142. Milligan, G., Bond, R. A. & Lee, M. Inverse agonism: pharmacological curiosity or potential therapeutic strategy? Trends Pharmacol. Sci. 16, 10–13 (1995).

    CAS  PubMed  Google Scholar 

  143. Leff, P. The two-state model of receptor activation. Trends Pharmacol. Sci. 16, 89–97 (1995).

    CAS  PubMed  Google Scholar 

  144. Kitbunnadaj, R. et al. Synthesis and structure-activity relationships of conformationally constrained histamine H3 receptor agonists. J. Med. Chem. 46, 5445–5457 (2003).

    CAS  PubMed  Google Scholar 

  145. Leurs, R. et al. Agonist-independent regulation of constitutively active G-protein-coupled receptors. Trends Biochem. Sci. 23, 418–422 (1998).

    CAS  PubMed  Google Scholar 

  146. Milligan, G. & Bond, R. A. Inverse agonism and the regulation of receptor number. Trends Pharmacol. Sci. 18, 468–474 (1997).

    CAS  PubMed  Google Scholar 

  147. Yates, S. L. et al. Cloning and expression of novel isoforms of the human histamine H3 receptor. Soc. Neurosci. Abstr. 27, 804.3 (2001).

    Google Scholar 

  148. Gallagher, M. & Yates, S. L. Histamine H3 receptor polynucleotides. WO Patent o3/042359A2 (2004).

  149. Tsui, P., Human histamine H3 gene variant-1. WO Patent 01/68665A1 (2001).

  150. Tsui, P., Human histamine H3 gene variant-2. WO Patent 6355452B1. (2002).

  151. Tsui, P., Human histamine H3 gene variant-3. WO Patent 01/68816A1. (2001).

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Acknowledgements

The authors would like to thank N. Carruthers (Johnson & Johnson PRD), S. Celanire (UCB Pharma), A. Hancock (Abbott Laboratories), K. Rimvall (Novo Nordisk) and H. Stark (Johann Wolfgang Goethe-University Frankfurt) for helpful discussions and sharing information before publication.

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  1. Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Faculty of Science, de Boelelaan 1083, Amsterdam, 1081 HV, The Netherlands

    Rob Leurs, Remko A. Bakker, Henk Timmerman & Iwan J. P. de Esch

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Correspondence to Rob Leurs.

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The authors act or have acted as consultants for various pharmaceutical companies active in the field of histamine receptors and have also received research payments from some companies in this field.

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DATABASES

Entrez Gene

GSK3β

H1 receptor

H2 receptor

H3 receptor

H4 receptor

PKB

OMIM

Alzheimer's disease

Shy–Drager syndrome

Glossary

PRODRUG

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism. It is generally designed to overcome problems associated with stability, toxicity, lack of specificity or limited (oral) bioavailability.

PARTIAL AGONIST

Whereas a full agonist produces the system maximal response, a partial agonist produces a maximal response that is below that of the system maximum (and that of a full agonist). As well as producing a sub-maximal response, partial agonists antagonise full agonists.

HYPOTHALAMUS

The hypothalamus is the region of the brain that controls body temperature, hunger and thirst, and circadian cycles.

INVERSE AGONIST

Inverse agonists reverse constitutive receptor activity, and are proposed to show selectively higher affinity for the inactive versus the active conformation of the receptor. In the absence of constitutive activity, inverse agonists function as competitive antagonists.

PHARMACOPHORE

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

NARCOLEPSY

Narcolepsy is a neurological disorder of sleep regulation that affects the control of sleep and wakefulness. The four classic symptoms are excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations.

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Leurs, R., Bakker, R., Timmerman, H. et al. The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 4, 107–120 (2005). https://doi.org/10.1038/nrd1631

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