Cherry-picked ligands at histamine receptor subtypes

doi:10.1016/j.neuropharm.2015.11.005

Neuropharmacology

Volume 106, July 2016, Pages 56-73

https://doi.org/10.1016/j.neuropharm.2015.11.005 Get rights and content

Highlights

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H1-R4Rs signaling pathways are discussed.
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Selected ligands representing key steps in drug development are provided.
•
SARs of most innovative and/or most important ligands are presented.
•
Pharmacological profiles of H1–H4R ligands are highlighted.
•
Selection criteria for optimal compound use in experimental set-up are discussed.

Abstract

Histamine, a biogenic amine, is considered as a principle mediator of multiple physiological effects through binding to its H₁, H₂, H₃, and H₄ receptors (H1–H4Rs). Currently, the HRs have gained attention as important targets for the treatment of several diseases and disorders ranging from allergy to Alzheimer's disease and immune deficiency. Accordingly, medicinal chemistry studies exploring histamine-like molecules and their physicochemical properties by binding and interacting with the four HRs has led to the development of a diversity of agonists and antagonists that display selectivity for each HR subtype. An overview on H1-R4Rs and developed ligands representing some key steps in development is provided here combined with a short description of structure–activity relationships for each class. Main chemical diversities, pharmacophores, and pharmacological profiles of most innovative H1–H4R agonists and antagonists are highlighted. Therefore, this overview should support the rational choice for the optimal ligand selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies.

This article is part of the Special Issue entitled ‘Histamine Receptors’.

Introduction

Histamine is a biogenic neurotransmitter, and since 1907, when it was first synthesized, is still in the center of general interest as it plays an important role in the regulation of several (patho)physiological conditions in central nervous system and peripheral tissues (Hough, 2001). The precise effects of histamine are exerted through stimulation of four different G-protein coupled receptor (GPCR) subtypes, namely H1–H4R (Fig. 1) (Arrang et al., 1988, Arrang et al., 1987, Arrang et al., 1983, Arrang et al., 1985a, Hill, 1990, Hill et al., 1997, Leurs et al., 2005, Lovenberg et al., 1999). The most characteristic roles for H1R activation are smooth muscle contraction and increases in vascular permeability, and many of its functions contribute to allergic responses. Thus, H1R antagonists have been very efficacious drugs for the treatment of allergies (Baraniuk, 1997). The H2R has been confirmed to function as a key modulator for gastric acid secretion, and H2R antagonists are largely used for the treatment of gastrointestinal ulcers (Arrang et al., 1988, Soll and Walsh, 1979). The H3R is primarily expressed in the human central nervous system (Arrang et al., 1988, Lovenberg et al., 1999). It functions as a presynaptic release-controlling receptor that regulates histamine, and also, as a hetero-receptor on non-histaminergic neurons modulating the release of norepinephrine, serotonin, GABA, acetylcholine, and other neurotransmitters (Arrang et al., 1988, Arrang et al., 1983, Blandina et al., 1996, Harada et al., 2004, Hill, 1990, Schlicker et al., 1993, Schlicker et al., 1989, Schlicker et al., 1990, Yokoyama et al., 1993).

Activation of the H1R leads to the mobilization of intracellular Ca²⁺ by activating the G_q family of G-proteins (Hill, 1990). The H2R signals through Gs G-proteins and receptor activation cause significant increases in cAMP, whereas the H3R couples to G_i/o, leading to moderate decreases in cAMP (Fig. 1) (Lovenberg et al., 1999, Nakamura et al., 2000). Also, signaling of H2R has been described to act through PLC/IP3 pathway by activating Gq family of G-proteins leading to mobilization of intracellular Ca²⁺ (Mitsuhashi et al., 1989, Smit et al., 1996b, Wellner-Kienitz et al., 2003). Recently, H4R was identified and showed a 35% amino acid homology with the H3R and much lower homologies to H1Rs and H2Rs (Liu et al., 2001, Morse et al., 2001, Nakamura et al., 2000, Nguyen et al., 2001, Oda et al., 2000, Zhu et al., 2001). The knowledge on the physiological and pathophysiological function based on H4R modulation is steadily increasing (Jablonowski et al., 2004, Jablonowski et al., 2003, Schneider and Seifert, 2016). However, preclinical data strongly suggest its potential therapeutic exploitation in allergy, inflammation, autoimmune disorders and possibly cancer. Hence, H4R can mediate chemotaxis and calcium influx in mast cells and eosinophils (Hofstra et al., 2003, O'Reilly et al., 2002, Stark et al., 2004, Walter and Stark, 2012).

Taken together, the four HRs couple with several different signaling pathways modulating various G-proteins (Fig. 1).

Section snippets

Histamine H1R

The H1R, including many other biogenic amine receptors, is one of the GPCR family members (see for a complete list e.g. http://www.gpcr.org/7tm/ or http://tools.gpcr.org/visualise/proteinselection) for which a tremendous input with the solved crystal structures has been done so far. In the early 1990s, a significant contribution to targeted research of H1R ligands has been provided by the cloning of the human H1R protein consisting of 487 amino acids (gene locus 3q25). Specifically synthesized

H1R agonists

Despite the fact that histamine (1) regulates various physiological and pathophysiological effects via H1Rs, the research area of the corresponding agonistic active compounds has been neglected for a long time (Fig. 3). Interestingly, two major structural elements can be differentiated in the histamine molecule, namely the imidazole ring and the aminoethyl side chain. A diversity of structural modifications in both parts has earlier been described (Gerhard and Schunack, 1980a, Gerhard and

H1R antagonists

The comparatively low number of H1R agonists is contrasted by the high number of diverse H1R antagonists. Based on pharmacological classification, they are grouped into different generations by considering their target as well as side effects profile. The first generation “antihistamines” consist of two aromatic elements connected by a mainly three membered bridge to a basic aliphatic tertiary amino functionality. Mepyramine (6), doxylamine (7), and doxepine (11) are few examples based on this

Histamine H2R

The H2R was recognized in 1972 following the discovery that numerous physiological effects of histamine, including the stimulation of gastric acid secretion, increase of heart rate, and inhibition of rat uterus contraction were not blocked by the H1R antagonist mepyramine (Black et al., 1972). Moreover, cloning of the H2R allowed studies which indicated strong expression in the stomach and brain (Gantz et al., 1991). Clinically, H2R antagonists shaped the treatment regimen of dyspepsia,

H2R agonists

In search for potent and selective H2R agonists, comprehensive structure–activity relationship studies have been conducted and led to the first H2R agonists, e.g. 4(5)-methylhistamine (16) which is actually now used as selective H4R agonist (Fig. 4) (Durant et al., 1975, Lim et al., 2005). Other small molecule ligands used as H2R agonists are the aminothiazole derivative amthamine (17) in which imidazole was replaced by a basic thiazole derivative (Eriks et al., 1993, Weinstein et al., 1976)

H2R antagonists

The finding that the thiourea derivative, N^α-thioguanylhomohistamine, acts as a partial H2R agonist in a gastric acid secretion test led to the development of the relatively weak H2R antagonist burimamide (23) which was the first selective compound for HR2s (Fig. 4) (Smit et al., 1996a, Smit et al., 1996c, Wyllie et al., 1972a, Wyllie et al., 1972b). Paradoxically, burimamide was later detected as potent histamine H3R antagonist and then also as a histamine H4R agonist (Smit et al., 1996a, Smit

Histamine H3R

Histamine receptors were largely linked with allergic and inflammatory reactions before the recognition of the histamine H3R in 1983 that proved its function as auto- as well as heteroreceptor at pre- and postsynaptic membranes and demonstrated its intense regulating influence on release of numerous central neurotransmitters (Arrang et al., 1988, Arrang et al., 1987, Arrang et al., 1983). Acting as an autoreceptor, H3R inhibits the synthesis and the release of histamine upon its activation. The

H3R agonists

At H3Rs, histamine (1) itself is a highly active agonist. Potent H3R agonists have been achieved by simple structural modifications of the histamine molecule. The methylated analog ³H-N^α-methylhistamine (NAMH, 30) (Arrang et al., 1987) is not selective for H₃R (vs H₁R, H₂R), but has found a wide use in radioligand competition binding assays due to its high affinity at rat H₃Rs (Arrang et al., 1983, Hill et al., 1997) and ready availability in tritiated form. R-(α)-methylhistamine (28) is highly

H3R antagonists

Several named antagonist ligands have figured noticeably in preclinical studies, with proved clear ability to release neurotransmitters and having efficacy in preclinical animal models. Consequently, this has encouraged ongoing research on improved agents with potency, selectivity, and better drug-likeness to facilitate clinical evaluation. Moreover, computer modeling strategies have been implemented widely, in recent years, for ligand docking and pharmacophore screening purposes (Levoin

Histamine H4R

The cloning of the H3R (Lovenberg et al., 1999) provided a template for the search of other histamine receptors, and resulted in the most recent discovery of histamine H4R. This concluded with six independent groups that have reported the cloning of the H4R (Leurs et al., 2009, Liu et al., 2001, Morse et al., 2001, Nakamura et al., 2000, O'Reilly et al., 2002, Oda et al., 2000, Zhu et al., 2001). Since that time much research has dedicated on the characterization of the receptor's function in

H4R agonists

The initially described H4R agonists were methylcyanoguanidine derivatives of 2,5-disubstituted tetrahydrofuranylimidazoles. These compounds show moderate affinity for the H4R and some selectivity over H3R (Lim et al., 2005). The best example is OUP-16 (49) with a high binding affinity for the human H4R and an 18-fold selectivity over H3R (Hashimoto et al., 2003, Leurs et al., 2009). Although firstly developed as a H2R-ligand, 4(5)-methylhistamine (16) is the most selective H4R agonist

H4R antagonists

The first potent and selective non-imidazole H4 antagonist was the indole carboxamide compound JNJ-7777120 (52). It was described to bind to the human H4R with high affinity and has excellent selectivity over a broad variety of GPCRs, including the H1R, H2R and H3R (Thurmond, 2015, Thurmond et al., 2004). Also, JNJ-7777120 possesses high affinity for the mouse and rat H4R (Thurmond, 2015, Thurmond et al., 2004) and it has been used widely as the reference compound to determine the role of H4R

Dual-acting HR antagonists

While the present medicinal chemistry efforts are mainly focused on selective ligands targeting GPCRs, and particularly on H1R, H3R and H4R selective antagonists/agonists, there were and, also, still are several efforts to develop dual acting H1R/H2R, H1R/H3R and H3R/H4R antagonists (Buschauer, 1988, Kottke et al., 2011, Sadek et al., 2013a, Scannell et al., 2004, Schulze et al., 1994, Taylor-Clark et al., 2005, Wiecek et al., 2011, Wolf et al., 1998). In this regard, a rational approach

Conclusion

Extensive medicinal chemistry efforts exploring structure–activity relationships with histamine and derivatives thereof led to the development of numerous novel ligands selectively targeting histamine H1–H4Rs. These ligands might be worthy in diseases including allergic conditions in which H1R seem to be predominant, peptic ulcer in which H2R are involved, narcolepsy, catalepsy, epilepsy and Alzheimer disorder in which H3R predominate, and inflammatory diseases in which the recently discovered

Conflicts of interest

The authors have no other conflicts of interest to disclose.

Acknowledgment

Support to BS was provided by a UAEU Program for Advanced Research (UPAR) 2013 Grant (# 31M126), UAE University. Support for this work was kindly provided to HS by the EU COST Actions CM1103 and CM1207 as well by DFG INST 208/664-1 FUGG.

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Some imidazole-based histamine H3R antagonists such as “2–18” have offered effective and significant protection in murine models of convulsion [105]. Indeed, L-histidine, the precursor of histamine reduced chemically-induced convulsions in rodents by triggering the central histaminergic system, increasing seizure threshold and decreasing seizure tendency and is mediated by histamine H1 receptors present in post synaptic area [67,106,107]. Histamine is synthesised in neurons located in the tuberomammillary nucleus of the posterior thalamus [108], and gives rise to diffuse projections that extend to almost the entire brain [109].
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Invited reviewCherry-picked ligands at histamine receptor subtypes

Highlights

Abstract

Introduction

Section snippets

Histamine H1R

H1R agonists

H1R antagonists

Histamine H2R

H2R agonists

H2R antagonists

Histamine H3R

H3R agonists

H3R antagonists

Histamine H4R

H4R agonists

H4R antagonists

Dual-acting HR antagonists

Conclusion

Conflicts of interest

Acknowledgment

Neuroscience

Eur. J. Pharmacol.

J. Mol. Graph. Model.

Physiol. Behav.

J. Allergy Clin. Immunol.

Neurobiol. Learn Mem.

Biochem. Pharmacol.

Drug Discov. Today

Eur. J. Pharmacol.

Biochem. Pharmacol.

Pharmacol. Biochem. Behav.

Biochem. Biophys. Res. Commun.

Drug Discov. Today

Biochem. Pharmacol.

Pharmacol. Biochem. Behav.

Eur. J. Med. Chem.

Eur. J. Pharmacol.

Behav. Brain Res.

Eur. J. Pharmacol.

Signal transduction mechanism of biased ligands at histamine H2 receptors

Biochem. J.

High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation

Proc. Natl. Acad. Sci. U. S. A.

Highly potent fluorescence-tagged nonimidazole histamine H3 receptor ligands

ChemMedChem

H3-receptors control histamine release in human brain

J. Neurochem.

Highly potent and selective ligands for histamine H3-receptors

Nature

Auto-inhibition of brain histamine release mediated by a novel class H3 of histamine receptor

Nature

Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET

J. Nucl. Med.

Influence of the novel histamine H(3) receptor antagonist ST1283 on voluntary alcohol consumption and ethanol-induced place preference in mice

Psychopharmacol. (Berl.)

Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H(3) receptor antagonist ST-1283

Drug Des. Dev. Ther.

Grapefruit juice-drug interactions

Br. J. Clin. Pharmacol.

A study of antagonist affinities for the human histamine H2 receptor

Br. J. Pharmacol.

Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist

Br. J. Pharmacol.

Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders

CNS Neurol. Disord. Drug Targets

A proof-of-concept study of the effect of a novel H3-receptor antagonist in allergen-induced nasal congestion

J. Allergy Clin. Immunol.

Histamine-induced actin polymerization in human eosinophils: an imaging approach for histamine H4 receptor

Cytom. A

Recent advances in the development of histamine H3 antagonists

Expert Opin. Ther. Pat.

Histamine H3 receptor as a drug discovery target

J. Med. Chem.

Histamine H3 receptor as a drug discovery target

J. Med. Chem.

Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

Br. J. Pharmacol.

In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer's disease

Neuropharmacology

Invited review
Cherry-picked ligands at histamine receptor subtypes