Structure−Activity Relationship of Triazafluorenone Derivatives as Potent and Selective mGluR1 Antagonists

Zheng, Guo Zhu; Bhatia, Pramila; Daanen, Jerome F.; Kolasa, Teodozyj; Patel, Meena; Latshaw, Steven P.; Kouhen, Odile F. El; Chang, Ruidong; Uchic, Marie E.; Miller, Loan; Nakane, Masaki; Lehto, Sonya G.; Honore, Marie P.; Moreland, Robert B.; Brioni, Jorge D.; Stewart, Andrew O.

doi:10.1021/jm0504407

Cited by 65 publications

(68 citation statements)

References 36 publications

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“…This is a nice example of species differences in the effects of allosteric modulators arising from the fact that the 7TM region of mGlu receptors is less conserved than the orthosteric ligand binding site. Subsequently, several novel negative allosteric mGlu1 receptor modulators (Table 6) were described that in functional in vitro assays had high potencies with IC 50 values in the low nanomolar range: (3,4- (Lavreysen et al, 2004), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo [3,2-a]benzimidazole-2-carboxamide hydrochloride (YM-298198) (Kohara et al, 2005) (Kohara et al, 2007), FTIDC (Suzuki et al, 2007a), 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (Fukuda et al, 2009) and compounds IX (Micheli et al, 2003) and X (Zheng et al, 2005) in Table 6. A number of additional negative allosteric mGlu1 receptor modulators (not shown in Table 6) have been described; their structures are given in the respective references (Mabire et al, 2005;Micheli et al, 2006;Di Fabio et al, 2007;Owen et al, 2007;Vanejevs et al, 2008;Sasikumar et al, 2009;Satoh et al, 2009).…”

Section: Allosteric Modulators Of the Mglu1 Receptor A Negative Allomentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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Section: Allosteric Modulators Of the Mglu1 Receptor A Negative Allomentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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“…The recently reported novel mGluR1 antagonist YM-298198 is thought to be a selective mGluR1 antagonist with oral activity while only potency toward rat, but not human, mGluR1 has been reported previously (Kohara et al, 2005). More recently, a new mGluR1 antagonist, A-841720, has been shown to be systemically active in rodent pain models (Zheng et al, 2005;El-Kouhen et al, 2006). However, the antagonistic activity of the compound toward human mGluR1 is 10-fold less potent than that toward rat mGluR1 and its selectivity between human mGluR1 and mGluR5 is not very high (about 30-fold) comparing other known noncompetitive mGluR1 antagonists.…”

mentioning

confidence: 98%

Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

Suzuki

Kimura²,

Satow³

et al. 2007

J Pharmacol Exp Ther

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A highly potent and selective metabotropic glutamate receptor (mGluR) 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2, 3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), is described. FTIDC inhibits, with equal potency, L-glutamate-induced intracellular Ca 2ϩ mobilization in Chinese hamster ovary cells expressing human, rat, or mouse mGluR1a. The IC 50 value of FTIDC is 5.8 nM for human mGluR1a and 6200 nM for human mGluR5. The maximal response in agonist concentration-response curves was reduced in the presence of higher concentrations of FTIDC, suggesting the inhibition in a noncompetitive manner. FTIDC at 10 M showed no agonistic, antagonistic, or positive allosteric modulatory activity toward mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8. FTIDC did not displace [ 3 H]L-quisqualate binding to human mGluR1a, indicating FTIDC is an allosteric antagonist. Studies using chimeric and mutant receptors of mGluR1 showed that transmembrane (TM) domains 4 to 7, especially Phe801 in TM6 and Thr815 in TM7, play pivotal roles in the antagonism of FTIDC. FTIDC inhibited the constitutive activity of mGluR1a, suggesting that FTIDC acts as an inverse agonist of mGluR1a. Intraperitoneally administered FTIDC inhibited face-washing behavior elicited by a group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine in mice at doses that did not produce motor impairment. Oral administration of FTIDC also inhibited the face-washing behavior. FTIDC is a highly potent and selective allosteric mGluR1 antagonist and a compound having oral activity without species differences in its antagonistic activity on recombinant human, mouse, and rat mGluR1. FTIDC could therefore be a valuable tool for elucidating the functions of mGluR1 not only in rodents but also in humans.Metabotropic glutamate receptors (mGluRs) are G proteincoupled receptors, and they are thought to contribute to the fine-tuning of fast synaptic response, neuronal excitability, and neurotransmitter release. To date, eight mGluR subArticle, publication date, and citation information can be found at

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“…The program GOLD (Genetic Optimisation for Ligand Docking) was used for docking the inhibitors into the ATP site of the Pim-1 kinase protein [16]. GOLD is an extensively used docking program used for assessing ligand protein interaction.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…In addition, there is evidence that the Hsp90 protein is accountable for correct folding and stabilization of the Pim-1 protein [15][16][17][18][19]. The underlying mechanisms have not been investigated and remain to be discovered.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Structure Activity Relationship and Molecular Docking of Pim-1 Kinase Inhibitors

Rathod¹

2017

Int J Biomed Data Min

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QSAR has established itself as an important means of virtual screening. Computational analysis of numerous drug molecules aided the facility to meaningfully screen specific ones for further use and experimentation. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) associated simulations were done and stochastic models were developed considering 55 molecules of hydroxyflavanone, thaizolidene2, 4-dione, pyridone derivatives against proviral insertion site of moloney murine leukemia virus. As part of the study, molecular field analysis (MFA) was done along with receptor surface analysis (RSA). Moreover, the generalization ability of the developed model was rigorously validated using 12 test set molecules. Molecular docking exercises were performed to analyze the protein structure using the crystal structure of PIM-1 kinase. Good correlation between predicted fitness scores and the observed activities was obtained. The presence of the hydroxyl groups in B ring instead of a ring was found crucial and playing important role for the compound activity. B ring substitution showed enhanced activity in this scenario. Further, the steric descriptor coefficient present near the ortho-position of N4 amine group indicates that any steric group increases the activity. GOLD was used for molecular docking of 55 molecules considered to target PIM-1 ATP binding site. GOLD based predicted fitness scores showed excellent correlation with the observations found in the available experimental outcomes.

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Structure−Activity Relationship of Triazafluorenone Derivatives as Potent and Selective mGluR1 Antagonists

Cited by 65 publications

References 36 publications

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

Quantitative Structure Activity Relationship and Molecular Docking of Pim-1 Kinase Inhibitors

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