Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists

Galambos, János; Wágner, Gábor; Nógrádi, Katalin; Bielik, Attila; Molnár, László; Bobok, Amrita; Horváth, Attila; Kiss, Béla; Kolok, Sándor; Nagy, J; Kurkó, Dalma; Bakk, Mónika Laura; Vastag, Mónika; Sághy, Katalin; Gyertyán, István; Gál, Krisztina; Greiner, István; Szombathelyi, Zsolt; Keserű, György M; Domány, György

doi:10.1016/j.bmcl.2010.06.075

Cited by 21 publications

(16 citation statements)

References 15 publications

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“…1C). In contrast, the potencies of mGlu 5 PAMs were often higher than their estimated affinities at the prototypical allosteric site labeled with Poon et al, 2004;Roppe et al, 2004;Chua et al, 2005;Tehrani et al, 2005;de Paulis et al, 2006;Kulkarni et al, 2006Kulkarni et al, , 2009Jaeschke et al, 2007;Milbank et al, 2007;Liu et al, 2008;Vanejevs et al, 2008;Felts et al, 2009Felts et al, , 2010Galambos et al, 2010;Rodriguez et al, 2010;Wágner et al, 2010;Zhang et al, 2010;Alagille et al, 2011;Gilbert et al, 2011;Lindemann et al, 2011;Sams et al, 2011;Weiss et al, 2011;Zou et al, 2011;Mueller et al, 2012). Dashed lines, unity; dotted lines, potency and affinity within 3-fold of each other; solid lines, 10-fold difference.…”

Section: Resultsmentioning

confidence: 99%

Investigating Metabotropic Glutamate Receptor 5 Allosteric Modulator Cooperativity, Affinity, and Agonism: Enriching Structure-Function Studies and Structure-Activity Relationships

et al. 2012

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Drug discovery programs increasingly are focusing on allosteric modulators as a means to modify the activity of G protein-coupled receptor (GPCR) targets. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, which allows for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator that can alter receptor pharmacological characteristics. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of orthosteric agonists. Established approaches for estimation of affinity and efficacy values for orthosteric ligands are not appropriate for allosteric modulators, and this presents challenges for fully understanding the actions of novel modulators of GPCRs. Metabotropic glutamate receptor 5 (mGlu 5 ) is a family C GPCR for which a large array of allosteric modulators have been identified. We took advantage of the many tools for probing allosteric sites on mGlu 5 to validate an operational model of allosterism that allows quantitative estimation of modulator affinity and cooperativity values. Affinity estimates derived from functional assays fit well with affinities measured in radioligand binding experiments for both PAMs and NAMs with diverse chemical scaffolds and varying degrees of cooperativity. We observed modulation bias for PAMs when we compared mGlu 5 -mediated Ca 2ϩ mobilization and extracellular signalregulated kinase 1/2 phosphorylation data. Furthermore, we used this model to quantify the effects of mutations that reduce binding or potentiation by PAMs. This model can be applied to PAM and NAM potency curves in combination with maximal fold-shift data to derive reliable estimates of modulator affinities.

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Section: Resultsmentioning

confidence: 99%

Investigating Metabotropic Glutamate Receptor 5 Allosteric Modulator Cooperativity, Affinity, and Agonism: Enriching Structure-Function Studies and Structure-Activity Relationships

et al. 2012

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“…Ligands L1 a , f , g , L11 a , f , g , L12 g , L14 g and L18 f , g and complexes [Rh(cod)( L14 g )]BF 4 and [Ir(cod)( L14 g )]BAr F were synthesized as previously reported . Substrates S1 , S2 , S5 , S6 – S7 , S8 , S9 , S10 – S11 , S12 – S14 , S17 – S23 , S24 , S25 , S26 , S31 , S33 – S38 , S39 – S43 , S44 – S45 and S46 were prepared following literature procedures. All other reagents are commercially available and were used as received.…”

Section: Methodsmentioning

confidence: 99%

Phosphite‐thioether/selenoether Ligands from Carbohydrates: An Easily Accessible Ligand Library for the Asymmetric Hydrogenation of Functionalized and Unfunctionalized Olefins

et al. 2019

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A large family of phosphite‐thioether/selenoether ligands has been easily prepared from accessible L‐(+)‐tartaric acid and D‐(+)‐mannitol and applied in the M‐catalyzed (M=Ir, Rh) asymmetric hydrogenation of a broad number of substrates (46 in total). Its highly modular architecture has been crucial to maximize the catalytic performance. Improving most of the reported approaches, this ligand family presents a broad substrate scope. By selecting the ligand parameters high enantioselectivities (ee's up to 99 %) have therefore been achieved in a broad range of both, functionalized and unfunctionalized substrates. Interestingly, both enantiomers of the hydrogenation products can be usually achieved by changing the ligand parameters.

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“…Recently, the research on imidazoles as antineuropathic agents is quite active. A lot of imidazoles have been demonstrated to possess good biological activities toward some neuropathic‐relative diseases such as epilepsy, AD, Parkinson's disease, schizophrenia, dementia, anxiety, and depression . The structures of imidazole‐based antineuropathic compounds are shown in Figure .…”

Section: Imidazoles As Antineuropathic Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

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Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists

Cited by 21 publications

References 15 publications

Investigating Metabotropic Glutamate Receptor 5 Allosteric Modulator Cooperativity, Affinity, and Agonism: Enriching Structure-Function Studies and Structure-Activity Relationships

Investigating Metabotropic Glutamate Receptor 5 Allosteric Modulator Cooperativity, Affinity, and Agonism: Enriching Structure-Function Studies and Structure-Activity Relationships

Phosphite‐thioether/selenoether Ligands from Carbohydrates: An Easily Accessible Ligand Library for the Asymmetric Hydrogenation of Functionalized and Unfunctionalized Olefins

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

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