SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide
The structure–activity relationship of a subtype selective mGlu2 potentiator, LY181837 is explored.
Section snippets
Acknowledgements
We thank Dr. Karl Dahnke and George E. Novak for their help with the synthesis of intermediates.
References (8)
- et al.
J. Med. Chem.
(1997)et al.J. Med. Chem.
(1999)et al.Stress
(2003) - et al.
Neuropharmacology
(2002)et al.Neuropharmacology
(2002)et al.Mol. Pharmacol.
(2003)et al.Neuropsychopharmacology
(2003) - et al.
Annu. Rep. Med. Chem.
(1997)et al.Neuropharmacology
(1999) - et al.
Neuropharmacology
(1998)
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Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases
2022, Pharmacology and TherapeuticsCitation Excerpt :In fact, substitution of these three critical amino acids with homologous ones from mGluR3 inactivates both LY487379 and BINA activity at mGluR2, whereas introduction of the three amino acids into mGluR3 at the right positions creates an active modulation site for this mGluR2-selective PAM on mGluR3 (Rowe et al., 2008). Other structurally novel and potent mGluR2 PAMs have been discovered later, including THIIC/LY2607540, CBiPES/LY566332, JNJ-40068782, JNJ-40411813, SAR218645 and AZD8529 (Barda et al., 2004; Caprioli et al., 2015; Fell et al., 2011; Griebel et al., 2016; Lavreysen et al., 2013; Lavreysen et al., 2015; Trabanco & Cid, 2013). These mGluR2 PAMs have been shown to be effective in animal models of anxiety, depression, drug addiction and schizophrenia (Caprioli et al., 2015; Fell et al., 2011; Galici et al., 2006; Griebel et al., 2016; Jin et al., 2010; Johnson et al., 2005; Justinova et al., 2015; Trabanco & Cid, 2013).
Reprint of Pharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2
2017, NeuropharmacologyCitation Excerpt :l-glutamate, (1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740, Fig. 1a; Schoepp et al., 1997); (2S)-2-Amino-2-((1S,2S)-2-carboxycycloprop-1-yl)-3-(9-xanthyl) propanoic acid disodium salt (LY351495; Kingston et al., 1998); (rac)-methyl-4-carboxyphenylglycine (MCPG), (2S,2′R,3′R)-2-(2′,3′-Dicarboxycyclopropyl)glycine (DCG-IV) and 2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)ethanesulfonamide hydrochloride (LY487379, Fig. 1b) are purchased from Tocris Cookson (Bristol, U.K.). 1-Butyl-4-[4-(2,6-dimethyl-pyridin-3-yloxy)-3-fluoro-phenyl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (PAM-1, Compound 22, Fig. 1c) (Cid-Nunez et al., 2008; Fraley, 2009); 2,2,2-Trifluoroethyl [3-(1-methyl-butoxy)-phenyl]-pyridine-3-ylmethyl-sulfonamide (2,2,2-TEMPS, Fig. 1d) (Barda et al., 2004); 3’-(8-Methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid (RO5488608, Fig. 1f) (Lundström et al., 2011) and the mGlu3 selective NAM [(S)-1-(5-Chloro-pyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichloro-benzyl)-amine (Britton et al., 2011) are synthesized at F. Hoffmann La Roche. The radioligands 2,2,2-Trifluoro-ethanesulfonic acid [3-(3,4-ditritio-1-methyl-butoxy)-phenyl]-pyridin-3-ylmethyl-amide, (3[H]-2,2,2-TEMPS, Fig. 1e) (specific activity 92 Ci/mmol), 3[H]-LY354740 (specific activity 43 Ci/mmol) (Schaffhauser et al., 1998) and 3[H]-HYDIA (specific activity 21.9 Ci/mmol) (Lundström et al. 2009) and not radiolabeled HYDIA (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid) are synthesized at F. Hoffmann La Roche by Drs. D. Muri, P. Huguenin, J. Wichmann, T. Woltering and H. Stadler (with a radiochemical purity >95%).
Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache
2017, Bioorganic and Medicinal Chemistry LettersPharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2
2016, NeuropharmacologyCitation Excerpt :This compound was chosen for this study because of its high potency as PAM at the mGlu2 receptor (GTPγS EC50 138 nM). 2,2,2-TEMPS (Fig. 1d), from the class of pyridylmethylsulfonamides, has been presented as a mGlu2 PAM with higher potency than LY487379 (Barda et al., 2004) and for this reason 2,2,2-TEMPS is utilized as reference and to develop a new high affinity radioligand that binds to the mGlu2 allosteric site. Several other mGlu2 PAM compounds, beside those mentioned in this study, were extensively characterized in previous publications and are reviewed in Trabanco and Cid (2013).
Synthesis of 1,1-diarylethylenes
2016, TetrahedronCitation Excerpt :Substituted germinal 1,1-diarylethylenes are present in many pharmacophores,1 including tamoxifen,2 bexarotene,3 iso-combretastatin A (isoCA-4),4 and ratanhine.5