Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands

Faghih, Ramin; Dwight, Wesley; Vasudevan, Anil; Dinges, Jürgen; Conner, Scott E.; Esbenshade, Timothy A.; Bennani, Youssef L.; Hancock, Arthur A.

doi:10.1016/s0960-894x(02)00648-0

Cited by 41 publications

(11 citation statements)

References 16 publications

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“…As can be seen from Fig. 10, the mean docking score for the hH 3 R actives lay in the cluster of [40,50] and was thus significantly shifted by a value of 20 to higher docking scores, when compared to the mean value of the distribution of WDI and MDB compounds ( [20,30]), thereby indicating that by docking into the hH 3 R binding site, significant higher scores were in average obtained for validated hH 3 R ligands. At the arbitrary chosen GoldScore cut-off of 40, at which 66.5% of the validated hH 3 R antagonists would have been retrieved, 87% of the WDI and MDB compounds were filtered out, resulting in 1720 structures, which were further analysed by visual inspection.…”

Section: Resultsmentioning

confidence: 92%

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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

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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.

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Section: Resultsmentioning

confidence: 92%

“…Main interactions between FUB836 and the hH 3 R binding site are listed in the Result section. Another residue in the hH 3 R, yet not interacting with FUB836, was methionine 6.55, which stabilised the second aromatic ring in biphenylic systems, such as A-331440 (results not shown) [50].…”

Section: Discussionmentioning

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

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“…Ciproxifan, proxyfan, and GT‐2331 ((1 S , 2 S )‐(+)‐4‐[2‐(5,5‐dimethyl‐hex‐1‐ynyl)‐cyclopropyl]‐1 H ‐imidazole) (Liu et al ., 2004) were synthesized at Abbott Laboratories. Nonlabelled A‐349821 ({4′‐[3‐(2 R ,5 R ‐dimethyl‐pyrrolidin‐1‐yl)‐propoxy]‐biphenyl‐4‐yl}‐morpholin‐4‐yl‐methanone) and other A‐compounds were prepared at Abbott laboratories as described previously (Faghih et al ., 2002, 2003a, 2003b; Turner et al ., 2003). Radiolabelled [ 3 H]N α MH was purchased from Perkin‐Elmer Life Sciences (Boston, MA, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

Detection of multiple H₃ receptor affinity states utilizing [³H]A‐349821, a novel, selective, non‐imidazole histamine H₃ receptor inverse agonist radioligand

Witte

Yao

Miller

et al. 2006

British J Pharmacology

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A‐349821 is a selective histamine H3 receptor antagonist/inverse agonist. Herein, binding of the novel non‐imidazole H3 receptor radioligand [3H]A‐349821 to membranes expressing native or recombinant H3 receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N‐α‐methylhistamine ([3H]NαMH). [3H]A‐349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3 receptors with 10‐fold higher affinity compared to rat H3 receptors. [3H]A‐349821 detected larger populations of receptors compared to [3H]NαMH. Displacement of [3H]A‐349821 binding by H3 receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3 receptor agonists was biphasic, suggesting recognition of both high‐ and low‐affinity H3 receptor sites. pKi values of high‐affinity binding sites for H3 receptor competitors utilizing [3H]A‐349821 were highly correlated with pKi values obtained with [3H]NαMH, consistent with labelling of H3 receptors by [3H]A‐349821. Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A‐349821, while displacement of [3H]A‐349821 binding by the H3 receptor agonist histamine was sensitive to GDP. In conclusion, [3H]A‐349821 labels interconvertible high‐ and low‐affinity states of the H3 receptor, and displays improved selectivity over imidazole‐containing H3 receptor antagonist radioligands. [3H]A‐349821 competition studies showed significant differences in the proportions and potencies of high‐ and low‐affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors. British Journal of Pharmacology (2006) 148, 657–670. doi:

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“…152) Due to QT prolongation A-329821 was sorted out from further development. 22) To advance brain penetration the carboxamide is replaced by a nitrile group and after additional modifications of the basic moiety in the western part of the molecule a 3-(dimethylamino)pyrrolidine containing compound 153) is further characterized: A-331440 is an inverse H 3 R agonist with good affinity (pK i ϭ8.6) and high selectivity to the targeted receptor. Despite similar pharmacokinetic characteristics it differs from A-329821 with regard to the brain/blood ratio (160).…”

Section: )mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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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...

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Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands

Cited by 41 publications

References 16 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

Detection of multiple H₃ receptor affinity states utilizing [³H]A‐349821, a novel, selective, non‐imidazole histamine H₃ receptor inverse agonist radioligand

Histamine H3 Receptor Antagonists Go to Clinics

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Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands

Cited by 41 publications

References 16 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

Detection of multiple H3 receptor affinity states utilizing [3H]A‐349821, a novel, selective, non‐imidazole histamine H3 receptor inverse agonist radioligand

Histamine H3 Receptor Antagonists Go to Clinics

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Detection of multiple H₃ receptor affinity states utilizing [³H]A‐349821, a novel, selective, non‐imidazole histamine H₃ receptor inverse agonist radioligand