A Robust and High-Capacity [35S]GTPγS Binding Assay for Determining Antagonist and Inverse Agonist Pharmacological Parameters of Histamine H3 Receptor Ligands

Miller, Thomas R.; Baranowski, John L.; Estvander, Brian R.; Witte, David G.; Carr, Tracy L.; Manelli, Arlene M.; Krueger, Kathleen M.; Cowart, Marlon; Brioni, Jorge D.; Esbenshade, Timothy A.

doi:10.1089/adt.2007.118

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…94) Since the fourth histamine receptor has been discovered, selectivity and function of H 3 R ligands is questioned and a reclassification of frequently used compounds takes place. 10,49,95) Instead of being a selective hH 3 R antagonist thioperamide (pK i ϭ7.2) 96) reveals comparable affinity at hH 4 R (pK i (hH 4 R)ϭ7.4). 52,54,97) Additionally, the compound possesses striking species differences with higher antagonist potency on rodent receptors (pK i (rH 3 R)ϭ8.4).…”

Section: Imidazole-based Antagonists As Pharmacological Toolsmentioning

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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Section: Imidazole-based Antagonists As Pharmacological Toolsmentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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“…The voluntary drinking paradigm was selected because it has the dual advantage of not requiring multiple diet control groups to control for paired feeding of a liquid diet as well as for allaying concern that the consumption of liquid diets may be stressful (Rasmussen et al, 2000), a potential confounder in fetal alcohol exposure studies. The second study objective was to determine whether the cognitionenhancing agent 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile (ABT-239), a nonimidazole antagonist of H 3 histamine receptors Miller et al, 2008) that reverses learning deficits in a variety of models including our current fetal ethanol exposure paradigm (Savage et al, 2010), would also reverse fetal ethanol-induced deficits in dentate gyrus LTP. The pharmacologic rationale for selecting ABT-239 was based on prior observations, suggesting that prenatal ethanol exposure diminished activity-dependent potentiation of glutamate release in hippocampal slices (Savage et al, 1998).…”

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confidence: 99%

Effects of the Cognition-Enhancing Agent ABT-239 on Fetal Ethanol-Induced Deficits in Dentate Gyrus Synaptic Plasticity

Varaschin¹,

Akers²,

Rosenberg³

et al. 2010

J Pharmacol Exp Ther

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Prenatal ethanol exposure causes deficits in hippocampal synaptic plasticity and learning. At present, there are no clinically effective pharmacotherapeutic interventions for these deficits. In this study, we examined whether the cognition-enhancing agent 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl) benzonitrile (ABT-239), a histamine H 3 receptor antagonist, could ameliorate fetal ethanol-induced long-term potentiation (LTP) deficits. Long-Evans rat dams consumed a mean of 2.82 g/kg ethanol during a 4-h period each day. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, offspring litter size, and birth weights were not different between ethanol-consuming and control groups. A stimulating electrode was implanted in the entorhinal cortical perforant path, and a recording electrode was implanted in the dorsal dentate gyrus of urethane-anesthetized adult male offspring. Baseline input/output responses were not affected either by prenatal ethanol exposure or by 1 mg/kg ABT-239 administered 2 h before data collection. No differences were observed between prenatal treatment groups when a 10-tetanus train protocol was used to elicit LTP. However, LTP elicited by 3 tetanizing trains was markedly impaired by prenatal ethanol exposure compared with control. This fetal ethanol-induced LTP deficit was reversed by ABT-239. In contrast, ABT-239 did not enhance LTP in control offspring using the 3-tetanus train protocol. These results suggest that histamine H 3 receptor antagonists may have utility for treating fetal ethanol-associated synaptic plasticity and learning deficits. Furthermore, the differential effect of ABT-239 in fetal alcohol offspring compared with controls raises questions about the impact of fetal ethanol exposure on histaminergic modulation of excitatory neurotransmission in affected offspring.Heavy or binge patterns of drinking during pregnancy can cause profound morphological and neurological aberrations in offspring called fetal alcohol syndrome (Lemoine et al., 1968;Jones and Smith, 1973). However, increasing evidence indicates that even moderate drinking during pregnancy can cause subtle, long-term behavioral and cognitive impairments in the absence of the birth defects associated with fetal alcohol syndrome (for review, see Kodituwakku, 2009). These behavioral deficits may not become apparent until the educational years (Streissguth et al., 1990;Jacobson et al., 1998;Hamilton et al., 2003) and may increase in severity as the child matures (Streissguth et al., 1994).The mechanisms by which prenatal ethanol exposure causes long-lasting impairments in learning and memory are not well understood. Our previous studies of Sprague-Dawley rats using a 5% ethanol liquid diet paradigm as a model of moderate drinking during pregnancy indicated that prenatal ethanol-exposed offspring exhibit performance deficits on increasingly challenging memory tasks (Sutherland et al., 2000;Weeber et al., 2001). These memory impairments are, in part...

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“…To assess the functionality of our compounds, we used the [ 35 S]GTPγS hH 3 R binding assay 10. 11 In this assay, inverse agonists and agonists respectively inhibit and stimulate basal [ 35 S]GTPγS binding, while neutral antagonists appear silent. As shown in Figure 4 a, all tested compounds generally displayed potent inverse agonism.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a New Class of Non‐imidazole Oxazoline‐Based Histamine H₃ Receptor (H₃R) Inverse Agonists

et al. 2009

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A Robust and High-Capacity [³⁵S]GTPγS Binding Assay for Determining Antagonist and Inverse Agonist Pharmacological Parameters of Histamine H₃ Receptor Ligands

Cited by 7 publications

References 36 publications

Histamine H3 Receptor Antagonists Go to Clinics

Histamine H3 Receptor Antagonists Go to Clinics

Effects of the Cognition-Enhancing Agent ABT-239 on Fetal Ethanol-Induced Deficits in Dentate Gyrus Synaptic Plasticity

Discovery of a New Class of Non‐imidazole Oxazoline‐Based Histamine H₃ Receptor (H₃R) Inverse Agonists

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A Robust and High-Capacity [35S]GTPγS Binding Assay for Determining Antagonist and Inverse Agonist Pharmacological Parameters of Histamine H3 Receptor Ligands

Cited by 7 publications

References 36 publications

Histamine H3 Receptor Antagonists Go to Clinics

Histamine H3 Receptor Antagonists Go to Clinics

Effects of the Cognition-Enhancing Agent ABT-239 on Fetal Ethanol-Induced Deficits in Dentate Gyrus Synaptic Plasticity

Discovery of a New Class of Non‐imidazole Oxazoline‐Based Histamine H3 Receptor (H3R) Inverse Agonists

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Product

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A Robust and High-Capacity [³⁵S]GTPγS Binding Assay for Determining Antagonist and Inverse Agonist Pharmacological Parameters of Histamine H₃ Receptor Ligands

Discovery of a New Class of Non‐imidazole Oxazoline‐Based Histamine H₃ Receptor (H₃R) Inverse Agonists