Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2☆

Herold, Franciszek; Izbicki, Łukasz; Chodkowski, Andrzej; Dawidowski, Maciej; Król, Marek; Kleps, Jerzy; Turło, Jadwiga; Wolska, Irena; Nowak, Gabriel; Stachowicz, Katarzyna

doi:10.1016/j.ejmech.2009.07.007

Cited by 15 publications

(3 citation statements)

References 35 publications

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“…A literature survey of known SERT inhibitors indicated that SSA-426 ( 2 , Figure ), a Wyeth Pharmaceuticals dual SERT/5-HT 1A receptor antagonist, has high affinity for rat SERT ( K i = 2.34 ± 0.59 nM) . The tetrahydropyridine indole portion of 2 appears to be important for SERT binding, as several high-affinity SERT ligands containing this chemical signature have been reported. − …”

Section: Resultsmentioning

confidence: 99%

Identification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization

Nolan

Lapinsky

Talbot

et al. 2011

ACS Chem. Neurosci.

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Ligand virtual screening (VS) using the vestibular binding pocket of a 3-D monoamine transporter (MAT) computational model followed by in vitro pharmacology led to the identification of a human serotonin transporter (hSERT) inhibitor with modest affinity (hSERT Ki = 284 nM). Structural comparison of this VS-elucidated compound, denoted MI-17, to known SERT ligands led to the rational design and synthesis of DJLDU-3-79, a molecular hybrid of MI-17 and dual SERT/5-HT1A receptor antagonist SSA-426. Relative to MI-17, DJLDU-3-79 displayed 7-fold improvement in hSERT binding affinity and a 3-fold increase in [3H]-serotonin uptake inhibition potency at hSERT/HEK cells. This hybrid compound displayed a hSERT:hDAT selectivity ratio of 50:1, and a hSERT:hNET (human norepinephrine transporter) ratio of >200:1. In mice, DJLDU-3-79 decreased immobility in the tail suspension test comparable to the SSRI fluvoxamine, suggesting that DJLDU-3-79 may possess antidepressant properties. This proof of concept study highlights MAT virtual screening as a powerful tool for identifying novel inhibitor chemotypes and chemical fragments for rational inhibitor design.

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Section: Resultsmentioning

confidence: 99%

Identification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization

Nolan

Lapinsky

Talbot

et al. 2011

ACS Chem. Neurosci.

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“…Herold et al .,[112] synthesized derivatives of 4-aryl-5, 6, 7, 8-tetrahydro-pyrido[1,2,-c] pyrimidine (93). These compounds contain the 3-(4 piperidyl)-1- H indole residue or its methoxy or 2- methyl derivatives.…”

Section: Pyrimidinementioning

confidence: 99%

Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review

et al. 2011

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Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is approved for the treatment of major depression (including paediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression.

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“…Vortioxetine acts as an SSRI, an agonist of the 5-HT 1A receptor, a partial agonist of the 5-HT 1B and an antagonist of the 5-HT 3 and 5-HT 7 receptors [23]. The research presented in this paper is a continuation of a long-term research project conducted in our department, where ligands are tested for a double binding affinity for both the SERT protein and 5-HT 1A receptors [24][25][26][27][28]. Two series of novel derivatives of 4-aryl-2H-pyrido[1,2-c]pyrimidine and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine were designed, based on lead compounds (I-IV) that had been synthesized previously by the same research group and had demonstrated a high affinity for both the 5-HT 1A receptors and SERT protein ( Figure 4) [26,27].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands

Król

Ślifirski

Kleps

et al. 2021

IJMS

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Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d.

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Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2☆

Cited by 15 publications

References 35 publications

Identification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization

Identification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization

Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review

Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands

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