Review
Post Screen
The histamine H3 receptor as a therapeutic drug target for CNS disorders

https://doi.org/10.1016/j.drudis.2009.02.011Get rights and content

The histamine H3 receptor plays a regulatory role in the pre-synaptic release of histamine and other neurotransmitters, making it an attractive target for CNS indications including cognitive disorders, narcolepsy, ADHD and pain. As more and more H3 antagonists/H3 inverse agonists progress through the clinic, knowledge is gained to define the profile of the ‘ideal’ compound in terms of specificity, pharmacokinetic parameters and both duration and magnitude of receptor occupancy. Whether a single compound profile for the treatment of different disorders can be defined remains to be seen.

Introduction

The histamine H3 receptor (H3R) is a G-protein-coupled receptor (GPCR) and one of the four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, as demonstrated by the successful development of antihistamines directed at the histamine H1 receptor (for the treatment of allergic reactions) and also at the histamine H2 receptor (which, by inhibiting gastric acid secretion, revolutionised the treatment of gastric ulcers). The H3R has been identified as a mainly pre-synaptic autoreceptor, regulating the release of histamine 1, 2, as well as a heteroreceptor on non-histaminergic neurons that is capable of regulating the release of many other important neurotransmitters, such as acetylcholine, norepinephrine, dopamine and serotonin (Fig. 1) 3, 4, 5, 6.

The H3R is expressed predominantly in the central nervous system (CNS), with highest expression in the cerebral cortex, hippocampal formation, basal ganglia and hypothalamus 7, 8. These brain regions have been associated with cognition (cortex and hippocampus), sleep and homeostatic regulation (hypothalamus). In addition, H3 receptors are located in regions involved in nociception (specific thalamic areas, dorsal root ganglia and spinal cord) and therefore, might offer treatment opportunities for different modalities of pain [9].

The physiology and pharmacology of the H3R is determined not only by its localisation and expression levels, but also by differential splicing. Today, more than 20 splice variants (isoforms) have been described but their functions have yet to be elucidated completely. Not all of these isoforms appear to be functional GPCRs but some of them might regulate functional isoforms by associating with them. A detailed review on H3R isoforms has been published recently by Bongers et al. [10]. Furthermore, in addition to agonist-induced signalling, the H3R is also constitutively active and capable of signalling independently of agonist both in vitro and in vivo [2], adding an additional layer of complexity.

Given its widespread distribution and its ability to affect multiple neurotransmitter systems, it is not surprising that modulation of H3R activity has been proposed for a broad range of indications such as Alzheimer's disease (AD), attention deficit hyperactivity disorder (ADHD), sleep disorders [11], pain and obesity. Detailed coverage of all these indications is beyond the scope of this review, for an overview the reader is referred to Wijtmans et al. [12]. We will instead focus on the prospects of H3R antagonists for the improvement of cognition and memory in certain disorders as well as for the treatment of sleep disorders such as narcolepsy. We will also discuss data supporting the use of H3R antagonists for pain. For these indications compounds are currently under evaluation in clinical trials. There is also information on an H3R antagonist (SCH 497079 from Schering-Plough) to enter a clinical trial for evaluating its effect on overweight and obese patients; the rationale for using H3R antagonists as anti-obesity treatment is therefore briefly summarised.

Section snippets

Cognitive dysfunction

Cognition is a highly complex phenomenon involving many different processes, most of which are still far from being understood. Many neurotransmitter systems, including acetylcholine, dopamine, serotonin and glutamate contribute to specific aspects of cognition. H3R antagonists have been found to increase not only the release of histamine, but also the release of norepinephrine, dopamine and acetylcholine 3, 4, 5, 6, thus making H3R antagonists an attractive drug target for cognitive disorders.

Common pre-clinical issues with H3R antagonists. What can we learn from them?

Early H3R antagonists/inverse agonists that reached the clinic were imidazole-containing compounds, such as Gliatech's clinical candidate GT-2331 (Table 1; Cipralisant, Perceptin® [38]), and have been previously reviewed [39]. The development of this class of imidazole-containing compounds was probably terminated because of the inherent risk associated with the inhibition of cytochrome P450 isoenzymes, resulting in unacceptable drug–drug interactions (DDIs) 40, 41, as well as complex H3R

BF2.649 (tiprolisant)

Bioprojet's H3R antagonist BF2.649 (Table 2) exhibits potent binding to native human (IC50 = 5.3 nm), rat (Ki = 17 nm) and mouse (Ki = 14 nm) cortical H3 receptors. Further in vitro profiling in our laboratory (and others [15]) suggests that BF2.649 has both a CYP 2D6 liability (IC50 = 0.4 μm) and potent hERG K+ channel blockade (IC50 = 0.49 μm). BF2.649 is also reported to have poor PK profiles in both rat and dog (5% and 2% bioavailability, respectively [15]). Despite these issues, BF2.649 has been

References (63)

  • K.E. Cannon et al.

    Inhibition of chemical and low-intensity mechanical nociception by activation of histamine H-3 receptors

    J. Pain

    (2005)
  • A.D. Medhurst

    Structurally novel histamine H-3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats

    Biochem. Pharmacol.

    (2007)
  • Y. Itoh

    Feeding-induced increase in the extracellular concentration of histamine in rat hypothalamus as measured by in vivo microdialysis

    Neurosci. Lett.

    (1991)
  • K. Ookuma

    Neuronal histamine in the hypothalamus suppresses food intake in rats

    Brain Res.

    (1993)
  • T. Morimoto

    Brain histamine and feeding behaviour

    Behav. Brain Res.

    (2001)
  • S. Celanire

    Histamine H-3 receptor antagonists reach out for the clinic

    Drug Discov. Today

    (2005)
  • J.F. Lau

    Ureas with histamine H-3-antagonist receptor activity – a new scaffold discovered by lead-hopping from cinnamic acid amides

    Bioorg. Med. Chem. Lett.

    (2006)
  • A.A. Hancock

    The challenge of drug discovery of a GPCR target: analysis of preclinical pharmacology of histamine H-3 antagonists/inverse agonists

    Biochem. Pharmacol.

    (2006)
  • F.U. Axe

    Three-dimensional models of histamine H-3 receptor antagonist complexes and their pharmacophore

    J. Mol. Graph. Model.

    (2006)
  • T.A. Esbenshade

    Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H-3 receptor antagonist

    Biochem. Pharmacol.

    (2004)
  • G.B. Fox

    Differential in vivo effects of H-3 receptor ligands in a new mouse dipsogenia model

    Pharmacol. Biochem. Behav.

    (2002)
  • P. Bonaventure

    Histamine H-3 receptor antagonists: from target identification to drug leads

    Biochem. Pharmacol.

    (2007)
  • V.J. Santora

    Novel H-3 receptor antagonists with improved pharmacokinetic profiles

    Bioorg. Med. Chem. Lett.

    (2008)
  • V.J. Santora

    A new family of H-3 receptor antagonists based on the natural product Conessine

    Bioorg. Med. Chem. Lett.

    (2008)
  • O. Roche et al.

    A new class of histamine H-3 receptor antagonists derived from ligand based design

    Bioorg. Med. Chem. Lett.

    (2007)
  • D. Lazewska

    Piperidine variations in search for non-imidazole histamine H3 receptor ligands

    Bioorg. Med. Chem.

    (2008)
  • A.M. Aronov et al.

    A model for identifying HERG K+ channel blockers

    Bioorg. Med. Chem.

    (2004)
  • A.J. Barbier

    Pharmacological characterization of JNJ-28583867, a histamine H3 receptor antagonist and serotonin reuptake inhibitor

    Eur. J. Pharmacol.

    (2007)
  • J.M. Arrang

    Auto-inhibition of brain histamine-release mediated by a novel class (H-3) of histamine-receptor

    Nature

    (1983)
  • S. Morisset

    High constitutive activity of native H-3 receptors regulates histamine neurons in brain

    Nature

    (2000)
  • E. Schlicker

    Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex

    Naunyn Schmiedebergs Arch. Pharmacol.

    (1988)
  • Cited by (169)

    • Ameliorating effects of histamine H3 receptor antagonist E177 on acute pentylenetetrazole-induced memory impairments in rats

      2021, Behavioural Brain Research
      Citation Excerpt :

      Moreover, other studies have indicated the protective effect of H3R antagonists/ inverse agonists in different acute seizures models including maximal electroshock (MES) and PTZ-induced seizure models [8,21–24]. Interestingly, H3R antagonists/inverse agonists gained an enormous consideration concerning their promising diverse applications in the treatment of different neuropsychiatric disorders including epilepsy, dementia, Alzheimer’s disease, autism spectrum disorder and cognitive deficits [8,11,23,25–34]. Moreover, the memory-enhancing property of H3R antagonists/ inverse agonists was long-established by applying various behavioral test paradigms including single-trial passive avoidance paradigm (STPAP), novel object recognition test (NOR) and Morris water maze test (MWM) [8,28,35].

    • Histamine H<inf>3</inf> receptor antagonists/inverse agonists: Where do they go?

      2019, Pharmacology and Therapeutics
      Citation Excerpt :

      Nociceptive pain is as a consequence of potential tissue injuries from outside or inside the body, whereas neuropathic pain is caused by damage or dysfunction of nerve fibers in nervous system. As an inflammatory mediator, histamine plays a pivotal role in nociceptive processes in both the central and peripheral nervous systems (Gemkow et al., 2009; Hough & Rice, 2011; Tiligada et al., 2009). In this respect, the participation of H3Rs in modulating pain, especially neuropathic pain, has attracted attention for the design of H3R-related therapeutic agents, although the function of H3R agonists and antagonists as pain relievers remains a debatable issue and maybe attributable to side-target effects such as sigma-1 receptor antagonism (Berlin et al., 2011; Riddy et al., 2019; Sander et al., 2008; Wijtmans, Leurs, & de Esch, 2007).

    View all citing articles on Scopus
    View full text