Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

Grychowska, Katarzyna; Olejarz-Maciej, Agnieszka; Blicharz, Klaudia; Pietruś, Wojciech; Karcz, Tadeusz; Kurczab, Rafał; Koczurkiewicz, Paulina; Doroż-Płonka, Agata; Latacz, Gniewomir; Keeri, Abdul Raheem; Piska, Kamil; Satała, Grzegorz; Pęgiel, Joanna; Trybała, Wojciech; Jastrzębska-Więsek, Magdalena; Bojarski, Andrzej J.; Lamaty, Frédéric; Partyka, Anna; Walczak, Maria; Krawczyk, Martyna; Malikowska‐Racia, Natalia; Popik, Piotr; Zajdel, Paweł

doi:10.1016/j.ejmech.2022.114329

Cited by 13 publications

(19 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compounds 1 – 5 , 6a , and 7 were obtained according to the previously reported procedure and the analytical data are in accordance with the literature [ 26 , 28 ]. Compounds 13 – 21 were converted to hydrochloride salts.…”

Section: Experimental Methodsmentioning

confidence: 87%

See 1 more Smart Citation

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

Self Cite

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

Section: Experimental Methodsmentioning

confidence: 87%

“…The key 1 H -pyrrolo[3,2- c ]quinoline synthon 5 was obtained in a multistep synthesis route, following the previously reported protocol ( Scheme 1 ) [ 28 ].…”

Section: Resultsmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Notably, the introduction of fluorine to bioactive compounds can lead to either an improvement or a deterioration of biological activity [ 4 , 7 , 16 , 17 ]. However, rules of thumb for fluorination to obtain highly potent compounds have not been defined thus far.…”

Section: Resultsmentioning

confidence: 99%

“…Bioactive compounds were extracted from the ChEMBL database version 26. Only compounds with reported direct interactions (target relationship type: "D") with annotation for 35 human aminergic GPCR 16 targets at the highest confidence level (target confidence score: 9) and exact measurements ("=") were selected. In addition, only well-defined potency measurements were taken into account (standard type: 'K i ', 'IC 50 ', 'EC 50 ', 'K b ', 'K d ', 'pK i ', 'pIC 50 ', 'pEC 50 ', 'pK b ', 'LogK i ', or 'pK d ') and standardized in the form of negative decadic logarithm values.…”

Section: Compounds and Activity Datamentioning

confidence: 99%

Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands

et al. 2023

Self Cite

View full text Add to dashboard Cite

Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug Administration (FDA). Herein, we identified and analyzed 898 target-based F-containing isomeric analog sets for SAR analysis in the ChEMBL database—FiSAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 FiSAR sets contain activity cliffs (ACs), defined as pairs of structurally similar compounds showing significant differences in affinity (≥50-fold change), where the change of fluorine position may lead up to a 1300-fold change in potency. The analysis of matched molecular pair (MMP) networks indicated that the fluorination of aromatic rings showed no clear trend toward a positive or negative effect on affinity. Additionally, we propose an in silico workflow (including induced-fit docking, molecular dynamics, quantum polarized ligand docking, and binding free energy calculations based on the Generalized-Born Surface-Area (GBSA) model) to score the fluorine positions in the molecule.

show abstract

“…In order to comprehensively analyze the selected SAR outcomes related to PZ-1922, we also included previously reported structural congeners from dual 5-HT 6 R/5-HT 3 R antagonists (PZ-1939, FPPQ), 10 as well as a class of selective MAO-B inhibitors (PZ-1771). 17 The effect of replacing a sulfonyl linker with a methylene one was examined in 5-HT 6 R comparing compounds PZ-1939 and A significant response (>50% inhibition) was obtained only for MAO-B, 5-HT 6 R, and 5-HT 3 R. Inhibition assay for MAO-A and binding assays for serotonin 5-HT 1A R, 5-HT 7 R, and D 2 Rs were performed according to the previously reported methods. 8,17 Binding experiments for adrenergic α 1 R, α 2A R, and β 1 R, dopamine D 3 , histaminergic H 1 R, muscarinic M 1 R, serotonin 5-HT 2A R, 5-HT 2B R, 5-HT 2C R, serotonin transporter SERT, and hERG channel were performed at Eurofins, France.…”

Section: ■ Introductionmentioning

confidence: 99%

Superiority of the Triple-Acting 5-HT₆R/5-HT₃R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT₆R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

Grychowska,

López-Sánchez,

Vitalis

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

The multifactorial origin and neurochemistry of Alzheimer’s disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT6R antagonism and interaction with 5-HT3R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT6R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD.

show abstract

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

Cited by 13 publications

References 58 publications

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

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

Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands

Superiority of the Triple-Acting 5-HT₆R/5-HT₃R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT₆R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

Contact Info

Product

Resources

About

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

Cited by 13 publications

References 58 publications

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

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

Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands

Superiority of the Triple-Acting 5-HT6R/5-HT3R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

Contact Info

Product

Resources

About

Superiority of the Triple-Acting 5-HT₆R/5-HT₃R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT₆R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats