Structure‐Activity Relationship Studies of CNS Agents, Part 25: 4,6‐Di(heteroaryl)‐2‐(<i>N</i>‐methylpiperazino)pyrimidines as New, Potent 5‐HT<sub>2A</sub> Receptor Ligands: A Verification of the Topographic Model

Mokrosz, Maria J.; Strękowski, Lucjan; Kozak, W. X.; Duszyńska, Beata; Bojarski, Andrzej J.; Kłodzińska, Aleksandra; Czarny, Agnieszka; Cegła, Marek; Deren‐Wesolek, A.; Chojnacka-Wójcik, E; Dove, Stefan; Mokrosz, Jerzy L.

doi:10.1002/ardp.19953280906

Cited by 22 publications

(24 citation statements)

References 15 publications

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“…The distances between groups crucial for activity, i.e. two aromatic centers and a basic nitrogen atom (or, following Andersen, the point (87), pizotifen) and then distance ranges between respective points were defined [60]. It was shown that the distances suggested previously by Andersen fit well into the determined ranges: In relation to both the above models, Westkaemper et al discussed geometric characteristics of 9-(aminomethyl)-9,10-dihydroanthracene (AMDA, 79) and its analogues (e.g.…”

Section: Chart 12mentioning

confidence: 99%

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Bojarski

2006

CTMC

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An overview of pharmacophore models, developed for different subtypes of serotonin receptors belonging to the GPCR family, is presented. Starting with early models for 5-HT1A and 5-HT2 receptor ligands, and ending with the latest ones for 5-HT6- and 5-HT7 receptors, as many as fifty others are briefly summarized. No models have been developed for 5-HT1F-, 5-HT2B- and 5-HT5B receptor ligands, and in the case of 5-HT1E- and 5-HT5A Rs only single pilot studies with non-selective tryptamine derivatives are reported. For all the other subtypes of 5-HTRs, various pharmacophore hypotheses--either qualitative and/or quantitative--are characterized by sets of ligands used for their generation, a templates for alignment, the computational methods applied and, eventually, interfeature distances and/or statistical results--if available.

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Section: Chart 12mentioning

confidence: 99%

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Bojarski

2006

CTMC

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“…The activity of 6-phenyl substituted compound 9 remained the same whereas the other compounds (13-15) were even less active. In our earlier papers dealing with pyrimidinepiperazines [10,11], 4,6-diaryl-substituted derivatives were always more active than monosubstituted ones. Thus it may be concluded that the methyl group in position 6 of a pyridine ring also brings about some interactions favorable for ligand-receptor complex formation.…”

Section: Resultsmentioning

confidence: 98%

“…As has been mentioned in the introduction, the majority of model compounds used for generating a 5-HT 2A antagonist pharmacophore contain a pyrimidine ring as the central core [10,11]. N-Methylpiperazine moiety in position 2 of pyrimidine supplies a basic nitrogen atom necessary for a proper ionic interaction with the respective aspartic acid (ASP155) of the 5-HT 2A receptor.…”

Section: Resultsmentioning

confidence: 99%

“…The first comprehensive 5-HT 2A topographic model, based on the structure of (+)-LSD (a highly potent nonselective serotoninergic agent), was proposed by Glennon et al in 1991 [7]. Several other models were later created by Höltje [8], Andersen [9], as well as by our research group [10,11].The last-mentioned model, developed from a series of 4,6-disubstituted 2-(1-piperazinyl)pyrimidines, defined three distances between terminal nitrogen atoms and two centers of aromatic substituents in the 5-HT 2A receptor antagonist. …”

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confidence: 99%

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Modification of the Structure of 4, 6‐Disubstituted 2‐(4‐Alkyl‐1‐piperazinyl)pyridines: Synthesis and Their 5‐HT_2A Receptor Activity

Paluchowska

Bojarski

Bugno

et al. 2003

Archiv der Pharmazie

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Structure-activity relationship studies of a series of novel 4, 6-disubstituted 2-(1-piperazinyl)pyridines were conducted to revise our model of serotonin 5-HT(2A) receptor antagonist. Target compounds were synthesized using the benzotriazole-assisted Katritzky method. The majority of those compounds were found to be selective 5-HT(2A)/5-HT(1A) receptor ligands, though less potent than their previously described pyrimidine counterparts. In particular, the three compounds 6-8 showed the highest 5-HT(2A) receptor affinity (K(i) = 34-78 nM) and were classified as 5-HT(2A) antagonists in in vivo experiments. The influence of the structural modifications on the in vitro results was discussed; however, the elucidation of the role of the central core system requires further studies.

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“…nists (54), and 2-or 4-(4-methylpiperazino) pyrimidines were described as 5-HT2A receptor antagonists (55). The pyrrolo- [2,3] pyrimidines are effective inhibitors of the protein-tyrosine kinase JAK3 (56).…”

Section: Discussionmentioning

confidence: 99%

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

Erdmann

Weiwad

Kilka

et al. 2010

Journal of Biological Chemistry

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The Ca 2؉ /calmodulin-dependent protein phosphatase calcineurin is a key mediator in antigen-specific T cell activation. Thus, inhibitors of calcineurin, such as cyclosporin A or FK506, can block T cell activation and are used as immunosuppressive drugs to prevent graft-versus-host reactions and autoimmune diseases. In this study we describe the identification of 2,6-diaryl-substituted pyrimidine derivatives as a new class of calcineurin inhibitors, obtained by screening of a substance library. By rational design of the parent compound we have attained the derivative 6-(3,4-dichloro-phenyl)-4-(N,N-dimethylaminoethylthio)-2-phenyl-pyrimidine (CN585) that noncompetitively and reversibly inhibits calcineurin activity with a K i value of 3.8 M. This derivative specifically inhibits calcineurin without affecting other Ser/Thr protein phosphatases or peptidyl prolyl cis/trans isomerases. CN585 shows potent immunosuppressive effects by inhibiting NFAT nuclear translocation and transactivation, cytokine production, and T cell proliferation. Moreover, the calcineurin inhibitor exhibits no cytotoxicity in the effective concentration range. Therefore, calcineurin inhibition by CN585 may represent a novel promising strategy for immune intervention.The activation and the precise interplay between signaling pathways are crucial for the successful initiation and progression of the immune response as a reaction of an antigen contact. In T cells the stimulation of the T cell receptor by a specific antigen leads to a calcium release from the intracellular stores and to a calcium release-activated Ca 2ϩ channel-mediated calcium influx into the cytoplasm which activates calmodulin and thereby the Ser/Thr-protein phosphatase calcineurin (1). Consequently, calcineurin represents a bottleneck in T cell receptor signaling and allows the modulation of T cell activation by low molecular compounds, such as cyclosporin A (CsA) 2 or tacrolimus (FK506) (2). The cyclic undecapeptide CsA and the macrolid FK506 bind to and inhibit the phosphatase activity of calcineurin only after interaction with their respective peptidyl prolyl cis/trans isomerases (PPIases), cyclophilins (Cyp), and FK506-binding proteins (FKBP) through a gain-of-function mechanism (3, 4). Based on their particular characteristic to bind the immunosuppressive drugs CsA and FK506, members of the Cyp and FKBP family of PPIases were also termed immunophilins (5). Among the many known PPIases, the most abundant isoforms, Cyp18 and FKBP12, were identified as major intracellular acceptor proteins for CsA and FK506, respectively. The PPIase activity of both enzymes is strongly inhibited by the immunosuppressive drugs (6), leading to many of serious side effects (e.g. nephrotoxicity, neurotoxicity, hypertension, fibrosis) that were observed in the prevention and therapy of graftversus-host reactions or autoimmune diseases (7-10). Therefore, CsA derivatives, such as [DAT-Sar] 3 CsA, were synthesized to obtain cyclophilin-independent calcineurin inhibitors (11). However, [DAT-Sar] ...

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Structure‐Activity Relationship Studies of CNS Agents, Part 25: 4,6‐Di(heteroaryl)‐2‐(N‐methylpiperazino)pyrimidines as New, Potent 5‐HT_2A Receptor Ligands: A Verification of the Topographic Model

Cited by 22 publications

References 15 publications

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Modification of the Structure of 4, 6‐Disubstituted 2‐(4‐Alkyl‐1‐piperazinyl)pyridines: Synthesis and Their 5‐HT_2A Receptor Activity

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

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Structure‐Activity Relationship Studies of CNS Agents, Part 25: 4,6‐Di(heteroaryl)‐2‐(N‐methylpiperazino)pyrimidines as New, Potent 5‐HT2A Receptor Ligands: A Verification of the Topographic Model

Cited by 22 publications

References 15 publications

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Modification of the Structure of 4, 6‐Disubstituted 2‐(4‐Alkyl‐1‐piperazinyl)pyridines: Synthesis and Their 5‐HT2A Receptor Activity

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

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Structure‐Activity Relationship Studies of CNS Agents, Part 25: 4,6‐Di(heteroaryl)‐2‐(N‐methylpiperazino)pyrimidines as New, Potent 5‐HT_2A Receptor Ligands: A Verification of the Topographic Model

Modification of the Structure of 4, 6‐Disubstituted 2‐(4‐Alkyl‐1‐piperazinyl)pyridines: Synthesis and Their 5‐HT_2A Receptor Activity