Elsevier

Biochemical Pharmacology

Volume 73, Issue 8, 15 April 2007, Pages 1084-1096
Biochemical Pharmacology

Histamine H3 receptor antagonists: From target identification to drug leads

https://doi.org/10.1016/j.bcp.2006.10.031Get rights and content

Abstract

The successful cloning and functional expression of the histamine H3 receptor in the late 1990s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H3 antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H3 receptor. Analysis of structural features common to several series of non-imidazole H3 receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H3 antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H3 antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H3 antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H3 antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H3 antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.

Introduction

Since its first pharmacological description as an endogenous substance [1], histamine has been found to exert tremendous influence over a variety of physiological processes. Most notable are its roles in the inflammatory “triple response” and in gastric acid secretion, which are mediated by H1[2] and H2[3] receptors, respectively. Antagonists of the histamine H1 and H2 receptors have been successful as “blockbuster” drugs for treating allergic conditions (allergic rhinitis) and gastric-acid-related disorders, respectively.

In the early 1970s, an understanding emerged that histamine was a neurotransmitter in the central nervous system [4], [5]. Histamine synthesizing neurons are located in the tuberomammillary nucleus of the hypothalamus and project widely throughout the brain to regions that include the cortex, the hippocampus, amygdala and striatum [6]. In 1983, a third subtype of histamine receptor, H3, was pharmacologically identified as a presynaptic autoreceptor on histamine neurons in the brain controlling the stimulated release of histamine [7]. In 1987, the development of the agonist R-α-methylhistamine and the antagonist thioperamide validated the existence of the H3 receptor [8]. The H3 receptor was also shown to be a presynaptic heteroreceptor in non-histamine containing neurons in both the central and peripheral nervous systems [9]. Consequently, there are many potential therapeutic applications for histamine H3 agonists and antagonists [10], [11], [12], [13]. Since the histamine H3 receptor is a presynaptic negative modulator of neurotransmitter release, it is rationalized that an H3 receptor antagonist would enhance neurotransmitter release. By virtue of its unique CNS localization (striatum, thalamus, cortex) relative to other neurotransmitter receptors, it is hypothesized that H3 receptor antagonists may produce a unique profile of CNS activation. In particular, activation of histaminergic neurotransmission leads to waking, improved cognition and suppression of food intake. By increasing the amount of histamine released from neurons, thereby promoting activation of H1 receptor, H3 antagonists increase waking [14]. H3 antagonists are also thought to improve cognitive function possibly via an increase of acetycholine release [14], [15]. The role of the H3 receptor in the regulation of body weight is more controversial [11], [16]. This paper describes the pharmacological characterization of several drug-like H3 antagonists towards the identification of a suitable lead.

Section snippets

Cloning and functional expression of the human histamine H3 receptor cDNA

Despite intensive efforts, the molecular identity of the H3 receptor remained elusive for 15 years. In 1998, the successful cloning and functional expression of the histamine H3 receptor by our group at J&JPRD greatly facilitated drug discovery efforts at this target [17], [18]. As part of a directed effort to discover novel G protein-coupled receptors through homology searching of expressed sequence tag databases, a partial clone (GPCR97) that had significant homology to biogenic amine

JNJ-6379490: a suitable tool for in vivo exploration of H3 function

Several series of lead compounds were identified by high throughput screening (HTS) including imidazopyridines (JNJ-280566), N-methylimidazoles (JNJ-132600) and indolizidines (JNJ-10266386). Chemical structures are shown in Fig. 1, and corresponding in vitro binding and functional data for human and rat H3 receptors are listed in Table 1. JNJ-280566, originally prepared for a calcium channel antagonist program [32], was found to have weak affinity for H3 (Table 1). Subsequent medicinal

JNJ-5207852: a novel diamine-based H3 antagonist

JNJ-5207852 exhibits high affinity for both human and rat H3 receptors and behaves as a neutral antagonist (Table 1) [34]. This compound does not bind to H1, H2, or H4 receptors and it retained its selectivity when tested in a CEREP panel containing approximately 50 G-protein coupled receptors, ion channels and other drug targets. [3H]JNJ-5207852 failed to exhibit any appreciable binding in H3 knockout mice, but exhibited patterns of binding in the cortex, hypothalamus and striatum of wild-type

JNJ-10181457: a short acting H3 antagonist

JNJ-10181457 (or RWJ-662733 [46]) is a potent and selective H3 neutral antagonist exhibiting a short residency in brain tissue. Its in vitro potency was ∼10 times lower at the rodent H3 receptor versus the human H3 receptor. JNJ-10181457 showed rapid brain penetration and good receptor occupancy in striatum (Fig. 4). Maximal receptor occupancy (∼85%) was achieved after 1 h following oral administration (10 mg/kg, Fig. 4A). The washout of JNJ-10181457 was much more rapid than that of JNJ-5207852 (

Conclusions

Following the cloning of the histamine H3 receptor cDNA, our group and others [11], [12], [13], [19] have synthesized and preclinically tested numerous potent H3 ligands. JNJ-6379490, JNJ-5207852 and JNJ-10181457 represent small molecule non-imidazoles that are potent and selective H3 antagonists. These “drug-like” molecules have been profiled in various in vivo models (see Table 2 for a summary of the results) and several therapeutic opportunities have emerged from these preclinical data. The

Acknowledgment

The assistance of Dr. Kevin Sharp, Kenway Hoey, the vivarium staff and the bioanalytical group at J&JPRD, La Jolla is gratefully acknowledged.

References (66)

  • E. Itoh et al.

    A histamine H3 receptor antagonist, powerfully suppresses peptide YY-induced food intake in rats

    Biol Psychiatr

    (1999)
  • F. Jia et al.

    Effects of histamine H3 antagonists and donepezil on learning and mnemonic deficits induced by pentylenetetrazol kindling in weanling mice

    Neuropharmacology

    (2006)
  • S. Nishino et al.

    Narcolepsy: genetic predisposition and neuropharmacological mechanisms

    Sleep Med Rev

    (2000)
  • A. Alves-Rodrigues et al.

    Pharmacological characterisation of the histamine H3 receptor in the rat hippocampus

    Brain Res

    (1998)
  • J.-S. Lin et al.

    Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat

    Brain Res

    (1990)
  • G. Vanni-Mercier et al.

    Waking selective neurons in the posterior hypothalamus and their response to histamine H3-receptor ligands: an electrophysiological study in freely moving cats

    Behav Brain Res

    (2003)
  • G.B. Fox 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

    (2002)
  • T. Sagvolden et al.

    Rodent models of attention-deficit/hyperactivity disorder

    Biol Psychiatr

    (2005)
  • G. Barger et al.

    Chemical structure and sympathomimetic action of amines

    J Physiol (London)

    (1911)
  • A.S.F. Ash et al.

    Receptors mediating some action of histamine

    Br J Pharmacol Chemother

    (1966)
  • J.W. Black et al.

    Definition and antagonism of histamine H2-receptors

    Nature

    (1972)
  • M. Baudry et al.

    H1 and H2 receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices

    Nature

    (1975)
  • J.C. Schwartz et al.

    Development of histaminergic systems in the newborn rat brain

    J Physiol (Paris)

    (1970)
  • J.M. Arrang et al.

    Autoinhibition of brain histamine release mediated by a novel class (H3) of histamine receptor

    Nature

    (1983)
  • J.M. Arrang et al.

    Highly potent and selective ligands for histamine H3-receptors

    Nature

    (1987)
  • S.J. Hill et al.

    International Union of Pharmacology. XIII. Classification of histamine receptors

    Pharmacol Rev

    (1997)
  • R. Leurs et al.

    The histamine H3-receptor. A target for developing new drugs

    Prog Drug Res

    (1992)
  • A.A. Hancock et al.

    Assessment of pharmacology and potential anti-obesity properties of H3 receptor antagonists/inverse agonists

    Expert Opin Investig Drugs

    (2005)
  • T.W. Lovenberg et al.

    Cloning and functional expression of the human histamine H3 receptor

    Mol Pharmacol

    (1999)
  • T.W. Lovenberg et al.

    Cloning of rat histamine H3 receptor reveals distinct species pharmacological profiles

    J Pharmacol Exp Ther

    (2000)
  • R. Leurs et al.

    Timmerman H, de Esch IJP. The histamine H3 receptor: from gene cloning to H3 receptor drugs

    Nat Rev Drug Discov

    (2005)
  • S. Cassar

    Cloning of the guinea pig H3 receptor

    Neuroreport

    (2000)
  • S.M. Ali et al.

    Design, synthesis, and structure-activity relationships of acetylene-based histamine H3 receptor antagonists

    J Med Chem

    (1999)
  • Cited by (138)

    • Neurochemistry of sleep

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    • New Frontiers

      2019, Sleep and ADHD: An Evidence-Based Guide to Assessment and Treatment
    View all citing articles on Scopus
    View full text