Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

Marcinkowska, Monika; Mordyl, Barbara; Fajkis-Zajączkowska, Nikola; Siwek, Agata; Karcz, Tadeusz; Gawalska, Alicja; Bucki, Adam; Żmudzki, Paweł; Partyka, Anna; Jastrzębska-Więsek, Magdalena; Pomierny, Bartosz; Walczak, Maria; Smolik, Magdalena; Pytka, Karolina; Mika, Kamil; Kotańska, Magdalena; Kołaczkowski, Marcin

doi:10.1016/j.ejmech.2022.115071

Cited by 5 publications

(18 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the given experimental model, the activity of hybrid 16 was compared to the efficacy of parent alcohol 6 (5-HT 6 antagonist part deprived of GABA function). GABA was not tested, as it does not produce antidepressant effects, as we reported previously …”

Section: Resultsmentioning

confidence: 99%

“…HPLC analyses were used to quantify the percentage of molecules that remained at each time point relative to the 0 min time point. Brain tissue stability assay: Brain homogenate was prepared according to a previous protocol . Compound 16 was dissolved in DMSO to achieve the concentration of 5 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…The mixture was incubated during 18 h period of time. Next, the following fluorescent dyes were used: Calcein AM (ThermoFisher), Hoechst 33342 (ThermoFisher), and MitoTracker (ThermoFisher) as indicated previously . The images were taken with Leica DMI8 microscopy.…”

Section: Methodsmentioning

confidence: 99%

“…In fact, selective 5-HT 6 antagonists hold great promise as small molecule therapeutics in neuropsychiatric diseases, due to their promising antidepressant-like efficacy in animal models . Continuing our previous research in this area, , in the present work, we explored the novel 5-HT 6 binding chemotypes bearing various heterocycles, which could be easily connected with the function of GABA to construct a series of bifunctional molecules 16 – 20 . Within the in vitro profiling cascade, we identified hybrid molecule 16 characterized by the most desirable receptor profile and drug-like properties.…”

Section: Introductionmentioning

confidence: 90%

See 3 more Smart Citations

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Marcinkowska

Mordyl

Siwek

et al. 2023

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT 6 receptor activity. The serotonin 5-HT 6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT 6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

See 2 more Smart Citations

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Marcinkowska

Mordyl

Siwek

et al. 2023

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, the development of dual-acting agents, which not only could relieve cognitive decline but may also produce antidepressant and anxiolytic effects [ 9 ] and antipsychotic [ 10 ] and neuroprotective properties [ 11 ], has gained considerable attention. A number of compounds combine antagonism at the 5-HT 6 R with serotonin type 2A receptor (5-HT 2A R) antagonism [ 12 , 13 ], serotonin type 3 receptor (5-HT 3 R) antagonism [ 10 ], serotonin type 4 receptor (5-HT 4 R) agonism [ 14 , 15 ], GABA-A agonism [ 16 ] acetylcholinesterase inhibition [ 17 ], or monoaminoxidase type B (MAO-B) inhibition [ 18 ]…”

Section: Introductionmentioning

confidence: 99%

Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT6 and D3R Affinity in the 1H-Pyrrolo[3,2-c]quinoline Series

et al. 2023

View full text Add to dashboard Cite

Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand–receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT6 receptor and D3 receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT6R affinity and more potent 5-HT6R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT6R/D3R antagonist; nevertheless, the proposed modifications did not improve the activity at D3R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT6R binding site; however, they are unfavorable for such interactions at D3R.

show abstract

MM165 - A Small Hybrid Molecule Modulates the Kynurenine Pathway and Attenuates Lipopolysaccharide-Induced Memory Deficits and Inflammation

Kotańska,

Łanocha,

Bednarski

et al. 2024

Neurochem Res

Self Cite

View full text Add to dashboard Cite

Cognitive dysfunctions are now recognized as core symptoms of various psychiatric disorders e.g., major depressive disorder. Sustained immune activation may leads to cognitive dysfunctions. Proin ammatory cytokines shunt the metabolism of tryptophan towards kynurenine and quinolinic acid may accumulate at toxic concentrations. This acid triggers an increase in neuronal nitric oxide synthase function and promotes oxidative stress. The searching for small molecules that can regulate tryptophan metabolites produced in the kynurenic pathway has become an important goal in developing treatments for various central nervous system diseases with an in ammatory component. Previously we have identi ed a small hybrid molecule -MM165 which signi cantly reduces depressive-like symptoms caused by in ammation induced by lipopolysaccharide administration. In the present study, we investigated whether this compound would mitigate cognitive de cits induced by lipopolysaccharide administration and whether treatment with it would affect the plasma or brain levels of quinolinic acid and kynurenic acid.Neuroin ammation was induced in rats by administering lipopolysaccharide at a dose of 0.5 mg/kg body weight for 10 days. We conducted two tests: novel object recognition and object location, to assess the effect on memory impairment in animals previously treated with lipopolysaccharide. In plasma collected from rats, the concentrations of C-reactive protein and tumor necrosis factor alfa were determined. The concentrations of kynurenic acid and quinolinic acid were determined in plasma and homogenates obtained from the cerebral cortex of rats. Interleukin 6 in the cerebral cortex of rats was determined.Additionally, the body mass and spontaneous activity were measured in rats. Our study shows that MM165 may mitigate cognitive de cits induced by in ammation after administration of lipopolysaccharide and alter the concentrations of tryptophan metabolites in the brain. Compounds exhibiting a mechanism of action analogous to that of MM165 may serve as foundational structures for the development of a new class of antidepressants.

show abstract

Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

Cited by 5 publications

References 64 publications

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT6 and D3R Affinity in the 1H-Pyrrolo[3,2-c]quinoline Series

MM165 - A Small Hybrid Molecule Modulates the Kynurenine Pathway and Attenuates Lipopolysaccharide-Induced Memory Deficits and Inflammation

Contact Info

Product

Resources

About

Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

Cited by 5 publications

References 64 publications

Dual Molecules Targeting 5-HT6 and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Dual Molecules Targeting 5-HT6 and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT6 and D3R Affinity in the 1H-Pyrrolo[3,2-c]quinoline Series

MM165 - A Small Hybrid Molecule Modulates the Kynurenine Pathway and Attenuates Lipopolysaccharide-Induced Memory Deficits and Inflammation

Contact Info

Product

Resources

About

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation