Design, synthesis and melatoninergic activity of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides

Tsotinis, Andrew; Panoussopoulou, Maria; Eleutheriades, Andreas; Davidson, Kathryn; Sugden, David

doi:10.1016/j.ejmech.2007.01.005

Cited by 21 publications

(7 citation statements)

References 28 publications

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“…A set of 29 active MT 2 receptor ligands belonging to 12 different chemical classes was collected from the literature (Table S1, Supporting Information). − The compounds included both agonists and antagonists, covering most of the chemical scaffolds so far identified for active melatoninergic ligands. , The selected chemotypes are characterized by diverse chemical structures, yet retaining the key pharmacophoric features of the melatonin receptor ligands, i.e., an aromatic nucleus, usually carrying a methoxy group, which is connected to an amide group through a short linker. The drug-like decoys were extracted from the ChemBridge data set and submitted to a filtering procedure to select decoys similar to the active melatoninergic ligands in terms of physicochemical properties (see Experimental section and Figure S1, Supporting Information), in order to avoid artificial enrichments .…”

Section: Resultsmentioning

confidence: 99%

“…A subset of 21 “inactive” melatonin receptor ligands from the 12 chemical classes of the 29 active compounds was retrieved from the literature (Table S4, Supporting Information). ,− ,,,,− ,− Additional ligands were classified as inactive when their potency was at least 10-fold lower than that of active ligands from the same class. New screening runs were performed on the 50 compound set, and the number of false positives, i.e., the number of inactive compounds found in the top 29 positions, is reported in Table .…”

Section: Resultsmentioning

confidence: 99%

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Structure-Based Virtual Screening of MT₂ Melatonin Receptor: Influence of Template Choice and Structural Refinement

Pala

Beuming

Sherman

et al. 2013

J. Chem. Inf. Model.

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Developing GPCR homology models for structure-based virtual screening requires the choice of a suitable template and refinement of binding site residues. We explored this systematically for the MT2 melatonin receptor, with the aim to build a receptor homology model that is optimized for the enrichment of active melatoninergic ligands. A set of 12 MT2 melatonin receptor models was built using different GPCR X-ray structural templates and submitted to a virtual screening campaign on a set of compounds composed of 29 known melatonin receptor ligands and 2560 drug-like decoys. To evaluate the effect of including a priori information in receptor models, 12 representative melatonin receptor ligands were placed into the MT2 receptor models in poses consistent with known mutagenesis data and with assessed pharmacophore models. The receptor structures were then adapted to the ligands by induced-fit docking. Most of the 144 ligand-adapted MT2 receptor models showed significant improvements in screening enrichments compared to the unrefined homology models, with some template/refinement combinations giving excellent enrichment factors. The discriminating ability of the models was further tested on the 29 active ligands plus a set of 21 inactive or low-affinity compounds from the same chemical classes. Rotameric states of side chains for some residues, presumed to be involved in the binding process, were correlated with screening effectiveness, suggesting the existence of specific receptor conformations able to recognize active compounds. The top MT2 receptor model was able to identify 24 of 29 active ligands among the first 2% of the screened database. This work provides insights into the use of refined GPCR homology models for virtual screening.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Structure-Based Virtual Screening of MT₂ Melatonin Receptor: Influence of Template Choice and Structural Refinement

Pala

Beuming

Sherman

et al. 2013

J. Chem. Inf. Model.

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“…Acting as pharmacodynamics targets . Some tetrahydroquinolines acting on ion channels compounds 25 – 27 [180–183] (Figure 5), membrane receptors compounds 28 – 35 [184–194] (Figure 6), steroid hormone receptors compounds 36 – 46 [21,195–205] (Figure 7), and nonsteroid hormone receptors compounds 47–54 [206–224] (Figure 8).…”

Section: The Strategies For Hydrogenationmentioning

confidence: 99%

Advances in the reduction of quinolines to 1,2,3,4‐tetrahydroquinolines

El‐Shahat

2021

Journal of Heterocyclic Chem

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The pursuit of modern sustainable chemistry has stimulated the development of innovative catalytic processes that enable chemical transformations to be performed under mild and clean conditions with high efficiency. Herein, we report that the hydrogenation of heteroaromatic compounds is one of the most efficient methods for the construction of heterocyclic skeletons, and only a few promising progress has been achieved. Transition metal‐catalyzed, a countless number of transition metals include have been used toward the development of homo/heterogeneous hydrogenation of quinolines via the most convenient route (Direct Hydrogenation) to obtain the corresponding tetrahydroquinoline derivatives.

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“…Selected tri‐, tetra‐, and pentacycle‐based melatonin receptor ligands. 29 : Epperson et al 108 ; 30: Landagaray et al 105 ; 31 : Lucini et al 55 ; 32 : Tsotinis et al 58 ; 33 : Bedini et al 46 ; 34 : Jellimann et al 47 ; 35 : Uchikawa et al 72 ; 36 : Tsotinis et al 65 ; 37 : Koike et al 90 ; 38, 39 & 40 : Davies et al 122 ; 41 : Spadoni et al 87 ; 42 : Landagaray et al 85 ; 43 : Kobayashi et al 33 ; 44 : Attia et al 29 ; 45 : Faust et al 113 …”

Section: The Pharmacophores (The Others Figure 5: Tri‐ and Tetra‐cycles)unclassified

Melatonin receptor ligands: A pharmaco‐chemical perspective

Boutin

Witt‐Enderby

Sotriffer

et al. 2020

Journal of Pineal Research

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Melatonin MT1 and MT2 receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT2‐selective agents—agonists, antagonists, or partial agonists—were reported, the field was lacking MT1‐selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri‐ or tetra‐cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype‐selective melatonin receptor antagonists “active” in vivo, which are critical to our understanding of melatonin and melatonin receptors’ role in basic physiology and disease.

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Design, synthesis and melatoninergic activity of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides

Cited by 21 publications

References 28 publications

Structure-Based Virtual Screening of MT₂ Melatonin Receptor: Influence of Template Choice and Structural Refinement

Structure-Based Virtual Screening of MT₂ Melatonin Receptor: Influence of Template Choice and Structural Refinement

Advances in the reduction of quinolines to 1,2,3,4‐tetrahydroquinolines

Melatonin receptor ligands: A pharmaco‐chemical perspective

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Design, synthesis and melatoninergic activity of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides

Cited by 21 publications

References 28 publications

Structure-Based Virtual Screening of MT2 Melatonin Receptor: Influence of Template Choice and Structural Refinement

Structure-Based Virtual Screening of MT2 Melatonin Receptor: Influence of Template Choice and Structural Refinement

Advances in the reduction of quinolines to 1,2,3,4‐tetrahydroquinolines

Melatonin receptor ligands: A pharmaco‐chemical perspective

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Product

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Structure-Based Virtual Screening of MT₂ Melatonin Receptor: Influence of Template Choice and Structural Refinement

Structure-Based Virtual Screening of MT₂ Melatonin Receptor: Influence of Template Choice and Structural Refinement