Histamine H3 receptor antagonists: From target identification to drug leads
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)
- et al.
The physiology of brain histamine
Prog Neurobiol
(2001) The challenge of drug discovery of a GPCR target: analysis of preclinical pharmacology of histamine H3 antagonists/inverse agonists
Biochem Pharmacol
(2006)- et al.
Recent medicinal chemistry of the histamine H3 receptor
Prog Med Chem
(2006) - et al.
Keynote review: histamine H3 receptor antagonists reach out for the clinic
Drug Discov Today
(2005) - et al.
The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders
Trends Pharmacol Sci
(2004) - et al.
Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system
Pharmacol Ther
(2004) - et al.
Molecular and pharmacological characterization of the mouse histamine H3 receptor
Eur J Pharmacol
(2003) - et al.
Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H3 receptor
Neuropharmacology
(2002) - et al.
Alternative splicing of the histamine H3 receptor mRNA at the third cytoplasmic loop is not detectable in humans
Mol Brain Res
(2000) - et al.
The H3 receptor is involved in cholecystokinin inhibition of food intake in rats
Life Sci
(2001)
A histamine H3 receptor antagonist, powerfully suppresses peptide YY-induced food intake in rats
Biol Psychiatr
Effects of histamine H3 antagonists and donepezil on learning and mnemonic deficits induced by pentylenetetrazol kindling in weanling mice
Neuropharmacology
Narcolepsy: genetic predisposition and neuropharmacological mechanisms
Sleep Med Rev
Pharmacological characterisation of the histamine H3 receptor in the rat hippocampus
Brain Res
Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat
Brain Res
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
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
Rodent models of attention-deficit/hyperactivity disorder
Biol Psychiatr
Chemical structure and sympathomimetic action of amines
J Physiol (London)
Receptors mediating some action of histamine
Br J Pharmacol Chemother
Definition and antagonism of histamine H2-receptors
Nature
H1 and H2 receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices
Nature
Development of histaminergic systems in the newborn rat brain
J Physiol (Paris)
Autoinhibition of brain histamine release mediated by a novel class (H3) of histamine receptor
Nature
Highly potent and selective ligands for histamine H3-receptors
Nature
International Union of Pharmacology. XIII. Classification of histamine receptors
Pharmacol Rev
The histamine H3-receptor. A target for developing new drugs
Prog Drug Res
Assessment of pharmacology and potential anti-obesity properties of H3 receptor antagonists/inverse agonists
Expert Opin Investig Drugs
Cloning and functional expression of the human histamine H3 receptor
Mol Pharmacol
Cloning of rat histamine H3 receptor reveals distinct species pharmacological profiles
J Pharmacol Exp Ther
Timmerman H, de Esch IJP. The histamine H3 receptor: from gene cloning to H3 receptor drugs
Nat Rev Drug Discov
Cloning of the guinea pig H3 receptor
Neuroreport
Design, synthesis, and structure-activity relationships of acetylene-based histamine H3 receptor antagonists
J Med Chem
Cited by (138)
Neurochemistry of sleep
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionHistamine H<inf>3</inf> receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation
2021, Bioorganic and Medicinal ChemistryImidazopyridine-based selective and multifunctional ligands of biological targets associated with psychiatric and neurodegenerative diseases
2019, European Journal of Medicinal ChemistryNew Frontiers
2019, Sleep and ADHD: An Evidence-Based Guide to Assessment and TreatmentJNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice
2017, Biochemical and Biophysical Research Communications