Genomic Cloning, Heterologous Expression and Pharmacological Characterization of a Human Histamine H1 Receptor

Backer, Marianne D. De; Gommeren, W.; Moereels, Henri; Nobels, G; Gompel, P. Van; Leysen, Josée E.; Luyten, Walter

doi:10.1006/bbrc.1993.2662

Cited by 127 publications

(106 citation statements)

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“…We recently became aware of the study of De Backer et al (1993) dealing with the cloning and characterisation of the human histamine HI receptor. While the data presented are similar to ours, the present study in our laboratory adds information on part of the 3' non-coding sequence and reports the stable expression of the HI receptor in CHO cells.…”

Section: Discussionmentioning

confidence: 99%

Stable Expression of Human H₁‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Moguilevsky

Varsalona

Noyer

et al. 1994

European Journal of Biochemistry

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A cDNA clone for the histamine HI receptor was isolated from a human lung cDNA library; it encoded a protein of 487 amino acids which showed characteristic features of G-protein-coupled receptors. The percentages of identity of the deduced amino acid sequence with bovine, rat and guinea pig H, histamine receptors were 82.6%, 79.4% and 73.3%, respectively, whereas these percentages decreased to 74.6%, 66% and 56.7% for the amino acid sequence of the third intracellular loop. The human H,-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector ; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H,-histamine-receptor antagonists and histamine. Northern blot analysis indicated the presence of two histamine HI receptor mRNAs of 3.5 kb and 4

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Section: Discussionmentioning

confidence: 99%

Stable Expression of Human H₁‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Moguilevsky

Varsalona

Noyer

et al. 1994

European Journal of Biochemistry

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“…The potential histamine H 1 receptor agonist and antagonist properties of Dimebon were evaluated using an in vitro guanosine 5Ј-3-O-(thio)triphosphate (GTP␥S) binding assay (De Backer et al, 1993). In brief, samples containing Dimebon or the H 1 antagonist pyrilamine were preincubated for 30 min with a membrane fraction from Chinese hamster ovary-K1 cells that were engineered to express the human H 1 receptor.…”

Section: Methodsmentioning

confidence: 99%

“…Because agonists of the histamine H 1 receptor have been implicated in memory, the agonist and (Ellman et al, 1961). antagonist properties of Dimebon were determined with an in vitro GTP␥S binding assay (De Backer et al, 1993) using a cell line engineered to express the human H 1 receptor. Consistent with an antagonist profile, Dimebon showed a concentration-dependent inhibition of histamine-induced GTP␥S binding with an IC 50 ϭ 76.5 nM.…”

Section: Pharmacology Of Dimebon's Procognitive Effects 751mentioning

confidence: 99%

Cognition-Enhancing Properties of Dimebon in a Rat Novel Object Recognition Task Are Unlikely to Be Associated with Acetylcholinesterase Inhibition orN-Methyl-d-aspartate Receptor Antagonism

Giorgetti¹,

Gibbons²,

Bernales³

et al. 2010

J Pharmacol Exp Ther

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Dimebon (dimebolin) treatment enhances cognition in patients withAlzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-Daspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 Ϯ 0.43, 14 Ϯ 5.1, and 172 Ϯ 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K i ϭ 105 Ϯ 18 M) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K i ϭ 0.54 Ϯ 0.05 M). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC 50 Ͼ 50 M), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.Dimebon (latrepirdine, dimebolin) is an investigational drug in Phase 3 clinical trials for the treatment of Alzheimer's disease (AD) and Huntington's disease (HD). Dimebon improved cognitive function in patients with AD during a 6-month placebo-controlled study with a 6-month open-label extension (Doody et al., 2008), and patients with HD showed some benefits in cognition in a 3-month Phase 2 study (Kieburtz et al., 2010). In the AD trial, patients treated with Dimebon also showed improvement over placebo in activities of daily living and in the behavioral and neuropsychiatric symptoms of AD, suggesting broad-based clinical improvement (Doody et al., 2008). The mechanism by which Dimebon exerts the favorable effects reported in these clinical studies is not clearly understood.Current AD therapeutics fall into two main pharmacologic classes: acetylcholinesterase (AChE) inhibitors, including donepezil, galantamine, and rivastigmine (Birks, 2006; These studies were funded by Medivation, Inc., San Francisco, California. Parts of these data were previously presented as follows: Article, publication date, and citation information can be found at

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“…The bovine H 1 receptor cDNA was cloned in 1991 by expression cloning in the classic Xenopus oocyte system (Yamashita et al, 1991). This led rapidly to the cloning of the receptor cDNA in several species, including human in 1993(De Backer et al, 1993Moguilevsky et al, 1994). The human gene was subsequently localized to chromosome 3p14-p21 (Le Coniat et al, 1994).…”

Section: A Receptor Structurementioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

et al. 2015

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Genomic Cloning, Heterologous Expression and Pharmacological Characterization of a Human Histamine H1 Receptor

Cited by 127 publications

References 0 publications

Stable Expression of Human H₁‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Stable Expression of Human H₁‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Cognition-Enhancing Properties of Dimebon in a Rat Novel Object Recognition Task Are Unlikely to Be Associated with Acetylcholinesterase Inhibition orN-Methyl-d-aspartate Receptor Antagonism

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

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Genomic Cloning, Heterologous Expression and Pharmacological Characterization of a Human Histamine H1 Receptor

Cited by 127 publications

References 0 publications

Stable Expression of Human H1‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Stable Expression of Human H1‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Cognition-Enhancing Properties of Dimebon in a Rat Novel Object Recognition Task Are Unlikely to Be Associated with Acetylcholinesterase Inhibition orN-Methyl-d-aspartate Receptor Antagonism

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

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Stable Expression of Human H₁‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells

Stable Expression of Human H₁‐histamine‐receptor cDNA in Chinese Hamster Ovary Cells