作者: Müller, Christa E. ; Namasivayam, Vigneshwaran ; Kostenis, Evi ; Stößel, Anne ; Junker, Anna ; Tian, Maoqun ; Köse, Meryem ; Hockemeyer, Jörg ; Pegurier, Cécile ; Voss, Jan H. ; Sarkar, Soumya ; Rashed, Mahmoud ; Liedtke, Andy J. ; Merten, Nicole ; Lewash, Michael ; Mahal, Ahmed ; Boshta, Nader M.

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds' potencies were evaluated in calcium mobilization and radioligand binding assays, and structure-activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3'-methoxy-[1,1'-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid (52, PSB-22269, K_i 8.91 nM) and its 3'-trifluoromethyl analog (54, PSB-24040, K_i 83.2 nM). Receptor-ligand docking studies revealed that the compounds' binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.

2008-01-01·European Journal of Pharmacology3区 · 医学

Inducible expression and pharmacological characterization of the mouse metabotropic glutamate 5b receptor

3区 · 医学

Article

作者: Mitch Kostich ; Gitali Mukhopadhyay ; Ellie D. Norris ; Thomas M. Laz ; Brian G. Salisbury

The metabotropic glutamate receptor subtype 5 (mGlu5) and glutamatergic neurotransmission are associated with the pathophysiology of disorders such as anxiety, depression or chronic pain. Human and rat mGlu5 receptors have been cloned and characterized previously. We now describe the cloning of the mouse mGlu5b receptor gene from adult mouse brain and its expression using an ecdysone-inducible system. This subtype has an extra 96 bp sequence which is inserted to the cytoplasmic tail and is identical to the insert present in human and rat mGlu5b. Mouse mGlu5b receptor expression was induced in HEK-293EcR cells by incubation with ponasterone A, an analogue of the insect hormone ecdysone. A fluorometric calcium transient assay system was used to characterize the basic pharmacologic profile of an isolated stable cell line. Quisqualic acid was the most potent receptor agonist (EC(50) approximately 7 nM) although the cells also responded to l-glutamic acid and the Group I-selective receptor agonist, 3,5-dihydroxyphenylglycine (3,5-DHPG). The calcium transients stimulated by these agonists were potently inhibited by reference allosteric mGlu5 antagonists - 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and 3-methoxy-5-(pyridine-2-ylethynyl)pyridine (methoxy-PEPy) (IC(50) ranges: 0.8-66 nM). The availability of this mouse mGlu5b receptor-expressing cell line will facilitate in vitro characterization of mGlu5 receptor-selective agonists or antagonists prior to in vivo pharmacologic testing.

2006-11-01·Nuclear Medicine and Biology4区 · 医学

In vitro and in vivo evaluation of [11C]MPEPy as a potential PET ligand for mGlu5 receptors

4区 · 医学

Article

作者: Kumar, J. S. Dileep ; Simpson, Norman R. ; Majo, Vattoly J. ; Prabhakaran, Jaya ; Arango, Victoria ; Underwood, Mark D. ; Parsey, Ramin V. ; Severance, Alin J. ; Van Heertum, Ronald L. ; Mann, J. John

Excessive activation via the metabotropic glutamate receptor subtype 5 (mGluR(5)) has been implicated in depression, neuropathic pain and other psychiatric, neurological and neurodegenerative diseases. A mGluR(5) radioligand for in vivo quantification by positron emission tomography (PET) would facilitate studies of the role of this receptor in disease and treatment. 3-Methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity antagonist at the mGluR(5) receptor was selected as a candidate ligand; a recent publication by Yu et al. [Nucl Med Biol 32 (2005) 631-640] presented initial micro-PET results for [(11)C]MPEPy with enthusiasm. Building on their efforts, we report as unique contributions (1) an improved chemical synthesis method, (2) the first data using human tissue, (3) phosphor images for rat brain preparations, (4) a novel comparison of anesthetic agents and (5) in vivo data in baboon. In vitro phosphor imaging studies of this ligand using human and rat brain tissue demonstrated high specific binding in the hippocampus, striatum and cortex with minimal specific binding in the cerebellum. In contrast, in vivo micro-PET studies in rats using urethane anesthesia, PET studies in baboons using isoflurane anesthesia and ex vivo micro-PET studies in unanesthetized rats each showed little specific binding in the brain. Despite the promising in vitro results, the low signal-to-noise ratio found in vivo does not justify the use of [(11)C]MPEPy as a PET radiotracer in humans.

100 项与 Neurodegenerative diseases(Consejo Superior de Investigaciones Científicas) 相关的药物交易

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