Experimental and Computational Structural Studies of 2,3,5-Trisubstituted and 1,2,3,5-Tetrasubstituted Indoles as Non-Competitive Antagonists of GluK1/GluK2 Receptors

Bartyzel, Agata; Kaczor, Agnieszka A.; Mahmoudi, Ghodrat; Masoudiasl, A.; Wróbel, Tomasz M.; Pitucha, Monika; Matosiuk, Dariusz

doi:10.3390/molecules27082479

Cited by 4 publications

(4 citation statements)

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“…Next, D2AAK5 was subjected to X-ray studies. Interatomic distances and bond angles of D2AAK5 are in the expected ranges [ 26 ] and are comparable to those observed in the related indole [ 7 , 17 , 18 , 19 , 27 , 28 ] and 3,4-dihydro-2 H -1,5-benzodioxepine [ 29 , 30 , 31 ] derivatives.…”

Section: Discussionsupporting

confidence: 73%

“…The molecular structure of D2AAK5 compound comprises two fused-ring system (6-fluoro-1 H -indole and 6-chloro-3,4-dihydro-2 H -1,5-benzodioxepine units) linked by N-methylethanaminium fragment. As in the previously reported compounds [ 7 , 17 , 18 , 19 ], all atoms of the indole group are essentially coplanar (r.m.s. deviation = 0.0115 Å for all non-H atoms), with the largest deviation from the least-squares plane (0.0164(2) Å) being for C8 atom.…”

Section: Resultssupporting

confidence: 56%

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Synthesis, Structural and Behavioral Studies of Indole Derivatives D2AAK5, D2AAK6 and D2AAK7 as Serotonin 5-HT1A and 5-HT2A Receptor Ligands

et al. 2023

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Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT1A and 5-HT2A receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT1A receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test.

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Section: Discussionsupporting

confidence: 73%

Section: Resultssupporting

confidence: 56%

Synthesis, Structural and Behavioral Studies of Indole Derivatives D2AAK5, D2AAK6 and D2AAK7 as Serotonin 5-HT1A and 5-HT2A Receptor Ligands

et al. 2023

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“…Proceeding with research on selective kainate receptor inhibitors, the group of Kaczor et al reported 1,2,3,5-tetrasubstituted indole derivatives, including the first non-competitive GluK2 receptor ligand known so far (54) [163]. Studies on these derivatives have contributed to the development of computational research on the structure of kainate receptor subunits and ligand binding sites [163,187,188].…”

Section: Non-competitive Antagonists and Channel Blockers Of Kainate ...mentioning

confidence: 99%

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

Chałupnik

Szymańska

2023

IJMS

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Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward ‘non-NMDA’ (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds.

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“…-Methoxy-6,11-dihydro-5H-benzo[a]carbazole(47) 34 (0.824 g, 3.31 mmol) was dissolved in DCM(40 mL) and MeOH (10 mL). The mixture was subjected to ozonolysis at −78 °C for 15 min and flushed with oxygen for 5 min to remove excess ozone.…”

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confidence: 99%

Antimalarial Dibenzannulated Medium-Ring Keto Lactams

Ren,

Wang,

Leas

et al. 2023

ACS Infect. Dis.

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We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5H-dibenzo[b,g]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD7.4 values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD7.4 values of <2) had the best metabolic stability (CLint values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC50 values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had Plasmodium falciparum IC50 values of 4.2 to 9.4 nM and in vitro selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani) but did have relatively high potency against Toxoplasma gondii, with IC50 values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1H)-quinolone transannular condensation products in vitro in culture medium and in vivo in mouse blood. The similar antiplasmodial potencies of three keto lactam–quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.

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Experimental and Computational Structural Studies of 2,3,5-Trisubstituted and 1,2,3,5-Tetrasubstituted Indoles as Non-Competitive Antagonists of GluK1/GluK2 Receptors

Cited by 4 publications

References 33 publications

Synthesis, Structural and Behavioral Studies of Indole Derivatives D2AAK5, D2AAK6 and D2AAK7 as Serotonin 5-HT1A and 5-HT2A Receptor Ligands

Synthesis, Structural and Behavioral Studies of Indole Derivatives D2AAK5, D2AAK6 and D2AAK7 as Serotonin 5-HT1A and 5-HT2A Receptor Ligands

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

Antimalarial Dibenzannulated Medium-Ring Keto Lactams

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