Medicinal Chemistry and Biological Properties of Non-Imidazole Histamine H3 Antagonists

Cowart, Marlon; Altenbach, Robert J.; Black, Lawrence A.; Faghih, Ramin; Zhao, Chen; Hancock, Arthur A.

doi:10.2174/1389557043403215

Cited by 70 publications

(35 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, several review articles have been published on the histamine H 3 receptor, [2] H 3 R isoforms, [3,4] on H 3 R antagonists [5,6] and agonists, [7] which summarise the current knowledge on this receptor. Briefly, the hH 3 R is a GPCR protein expressed presynaptically in several regions of the central and peripheral nervous system where it functions either as an autoreceptor regulating the release of histamine from histaminergic neurons or as an heteroreceptor regulating the release of several other neurotransmitters.…”

Section: Introductionmentioning

confidence: 99%

“…In order to find new hH 3 R ligands, initially, derivatives of the intrinsic ligand histamine were generated leading to the class of imidazolecontaining compounds [for a review see 6,7]. Due to several potential drawbacks of the imidazole-moiety (interaction with P450 enzymes, substrate of the inactivating enzyme, histamine N s -methyl transferase, and low CNS penetration 1 ) great effort was put into the replacement of this moiety, resulting in the nowadays heterogeneous class of non-imidazole ligands containing mostly piperidine, pyrrolidine or structurally related groups [10, for a review see 5,7]. In most cases new compounds were designed from scratch or by variation of hits found during in vitro screening of large compound libraries.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

The human histamine H 3 receptor (hH 3 R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH 3 R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH 3 R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH 3 R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH 3 R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [ 3 H]N a -methylhistamine binding assay. The compounds tested showed affinities at hH 3 R with K i values ranging from 0.079 to 6.3 lM.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.…”

mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

View full text Add to dashboard Cite

INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

show abstract

“…Thus, nonimidazole H 3 receptor antagonists may offer greater therapeutic potential in man. Recent reports from a number of industrial and academic laboratories (Apodaca et al, 2003;Chai et al, 2003;Miko et al, 2003;Zaragoza et al, 2004) have described the properties of novel nonimidazole H 3 receptor antagonists (for review, see Cowart et al, 2004b). In addition, we have reported on the pharmacological properties of the nonimidazole, aryloxyalkyl piperazine-based H 3 receptor antagonists, A-304121, A-317920 Fox et al, 2003), and A-349821 (Esbenshade et al, 2004).…”

mentioning

confidence: 99%

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H₃ Receptor Antagonist with Drug-Like Properties

Esbenshade¹,

Fox²,

Krueger³

et al. 2004

J Pharmacol Exp Ther

100

View full text Add to dashboard Cite

Histamine H 3 receptor antagonists are being developed to treat a variety of neurological and cognitive disorders that may be ameliorated by enhancement of central neurotransmitter release. Here, we present the in vitro pharmacological and in vivo pharmacokinetic profiles for the nonimidazole, benzofuran ligand ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] and compare it with several previously described imidazole and nonimidazole H 3 receptor antagonists. ABT-239 binds to recombinant human and rat H 3 receptors with high affinity, with pK i values of 9.4 and 8.9, respectively, and is over 1000-fold selective versus human H 1 , H 2 , and H 4 histamine receptors. ABT-239 is a potent H 3 receptor antagonist at recombinant human and rat receptors, reversing agonist-induced changes in cAMP formation (pK b ϭ 7.9 and 7.6, respectively), guanosine 5Ј-O-(3-[ ]GTP␥S binding at both rat and human H 3 receptors with respective pEC 50 values of 8.9 and 8.2. ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t 1/2 values ranging from 4 to 29 h, corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%. Thus, ABT-239 is a selective, nonimidazole H 3 receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties.Histamine H 3 receptors are G protein-coupled receptors that function as central autoreceptors to modulate the release of histamine (Arrang et al., 1983). H 3 receptors also function as heteroreceptors, regulating the release of other important neurotransmitters such as acetylcholine, dopamine, norepinephrine, and serotonin, among others (Blandina et al., 1998) that seem to play a role in attention, vigilance, and cognition. H 3 receptor antagonists enhance the release of these neurotransmitters and, thus, may be potential human therapeutic agents for the treatment of disorders associated with attentional and cognitive deficits, such as attention deficit/hyperactivity disorder, Alzheimer's Disease, mild cognitive impairment, and schizophrenia (Leurs et al., 1998).Since the cloning of the human and rat H 3 receptors

show abstract

Medicinal Chemistry and Biological Properties of Non-Imidazole Histamine H3 Antagonists

Cited by 70 publications

References 0 publications

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Histamine H3 Receptor Antagonists Go to Clinics

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H₃ Receptor Antagonist with Drug-Like Properties

Contact Info

Product

Resources

About

Medicinal Chemistry and Biological Properties of Non-Imidazole Histamine H3 Antagonists

Cited by 70 publications

References 0 publications

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Histamine H3 Receptor Antagonists Go to Clinics

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H3 Receptor Antagonist with Drug-Like Properties

Contact Info

Product

Resources

About

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H₃ Receptor Antagonist with Drug-Like Properties