Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists.


:The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2R and D3R have rendered the development of D3R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D3R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu2.64 and Phe7.39 and the packing at the junction of helices may affect the specificity for D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed a subpicomolar agonist activity at D3R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D3R ligands.






Cao Y,Sun N,Zhang J,Liu Z,Tang YZ,Wu Z,Kim KM,Cheon SH




Has Abstract


2018-06-14 00:00:00














  • Structure-Based Design, Synthesis by Click Chemistry and in Vivo Activity of Highly Selective A3 Adenosine Receptor Agonists.

    abstract::2-Arylethynyl derivatives of (N)-methanocarba adenosine 5'-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol-1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moie...


    pub_type: 杂志文章


    authors: Tosh DK,Paoletta S,Chen Z,Crane S,Lloyd J,Gao ZG,Gizewski ET,Auchampach JA,Salvemini D,Jacobson KA

    更新日期:2015-01-01 00:00:00

  • A systematic analysis of atomic protein-ligand interactions in the PDB.

    abstract::As the protein databank (PDB) recently passed the cap of 123 456 structures, it stands more than ever as an important resource not only to analyze structural features of specific biological systems, but also to study the prevalence of structural patterns observed in a large body of unrelated structures, that may refle...


    pub_type: 杂志文章


    authors: Ferreira de Freitas R,Schapira M

    更新日期:2017-10-01 00:00:00

  • Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors.

    abstract::Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an ...


    pub_type: 杂志文章


    authors: Nair RN,Mishra JK,Li F,Tortosa M,Yang C,Doherty JR,Cameron M,Cleveland JL,Roush WR,Bannister TD

    更新日期:2016-05-01 00:00:00

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    abstract::Three series of compounds were designed, synthesized and evaluated for their in vitro anticancer activity against a procaspase-3 over-expression cancer cell line (U937) and a procaspase-3 no-expression cancer cell line (MCF-7) to rule out off-target effects. Biological evaluation led to the identification of a series ...


    pub_type: 杂志文章


    authors: Ma J,Ni X,Gao Y,Huang K,Liu J,Wang Y,Chen R,Wang C

    更新日期:2019-02-25 00:00:00

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    abstract::In the present work, coumarin based pyrazolines (7a-g) have been synthesized and investigated for their in vitro and in vivo anti-inflammatory potential. Amongst the synthesized compounds, compounds 7a, 7d and 7f exhibited significant in vitro anti-inflammatory activity as compared to the standard etoricoxib. Keeping ...


    pub_type: 杂志文章


    authors: Chandel P,Kumar A,Singla N,Kumar A,Singh G,Gill RK

    更新日期:2019-01-23 00:00:00

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    abstract::Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, EC is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7). NPP1 hydrolyzes a wide range of phosphodiester bonds, e.g. in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5'...


    pub_type: 杂志文章,评审


    authors: Lee SY,Müller CE

    更新日期:2017-02-09 00:00:00

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    pub_type: 杂志文章


    authors: Santos ARN,Sheldrake HM,Ibrahim AIM,Danta CC,Bonanni D,Daga M,Oliaro-Bosso S,Boschi D,Lolli ML,Pors K

    更新日期:2019-06-27 00:00:00

  • Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.

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    pub_type: 杂志文章


    authors: Rye CS,Chessum NE,Lamont S,Pike KG,Faulder P,Demeritt J,Kemmitt P,Tucker J,Zani L,Cheeseman MD,Isaac R,Goodwin L,Boros J,Raynaud F,Hayes A,Henley AT,de Billy E,Lynch CJ,Sharp SY,Te Poele R,Fee LO,Foote KM,Gree

    更新日期:2016-08-01 00:00:00

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    pub_type: 杂志文章,评审


    authors: Wells CI,Kapadia NR,Couñago RM,Drewry DH

    更新日期:2017-12-08 00:00:00

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    pub_type: 杂志文章


    authors: Kundu S,Bansal S,Muthukumarasamy KM,Sachidanandan C,Motiani RK,Bajaj A

    更新日期:2017-10-31 00:00:00

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    pub_type: 杂志文章


    authors: Zhang X,Liu T,Wang B,Gao Y,Liu P,Li M,Du L

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    abstract::The phenol of 1-(3-(1H-imidazol-1-yl)propyl)-3-(4-hydroxy-3-methoxyphenyl)thiourea was selectively carbon-11 labelled to generate [11C]PBD150 in 7.3% yield from [11C]methyl triflate (non-decay corrected; radiochemical purity ≥95%, specific activity = 5.7 Ci/µmol, n=5). Evaluation of [11C]PBD150 by small animal PET ima...


    pub_type: 杂志文章


    authors: Brooks AF,Jackson IM,Shao X,Kropog GW,Sherman P,Quesada CA,Scott PJ

    更新日期:2015-06-01 00:00:00

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    pub_type: 杂志文章


    authors: Denya I,Malan SF,Enogieru AB,Omoruyi SI,Ekpo OE,Kapp E,Zindo FT,Joubert J

    更新日期:2018-01-16 00:00:00

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    abstract::[This corrects the article DOI: 10.1039/C0MD00060D.]. ...


    pub_type: 已发布勘误


    authors: Chen T,Mei WJ,Wong YS,Liu J,Liu Y,Xie HS,Zheng WJ

    更新日期:2018-03-19 00:00:00

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    pub_type: 杂志文章


    authors: Yu Z,Brannigan JA,Rangachari K,Heal WP,Wilkinson AJ,Holder AA,Leatherbarrow RJ,Tate EW

    更新日期:2015-10-08 00:00:00

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    pub_type: 杂志文章


    authors: Da C,Telang N,Hall K,Kluball E,Barelli P,Finzel K,Jia X,Gupton JT,Mooberry SL,Kellogg GE

    更新日期:2013-01-01 00:00:00

  • Synthesis and antitumor mechanism of a new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands.

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    pub_type: 杂志文章


    authors: Zou BQ,Qin QP,Bai YX,Cao QQ,Zhang Y,Liu YC,Chen ZF,Liang H

    更新日期:2017-02-01 00:00:00

  • Discovery of a tetrazolyl β-carboline with in vitro and in vivo osteoprotective activity under estrogen-deficient conditions.

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    pub_type: 杂志文章


    authors: Karvande A,Khan S,Khan I,Singh D,Khedgikar V,Kushwaha P,Ahmad N,Kothari P,Dhasmana A,Kant R,Trivedi R,Chauhan PMS

    更新日期:2018-06-12 00:00:00

  • Phenotype-based variation as a biomarker of sensitivity to molecularly targeted therapy in melanoma.

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    pub_type: 杂志文章


    authors: Senses KM,Ghasemi M,Akbar MW,Isbilen M,Fallacara AL,Frankenburg S,Schenone S,Lotem M,Botta M,Gure AO

    更新日期:2017-01-01 00:00:00

  • Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells.

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    pub_type: 杂志文章


    authors: Byun HS,Pyne S,Macritchie N,Pyne NJ,Bittman R

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    pub_type: 杂志文章


    authors: Unsal-Tan O,Tüylü Küçükkılınç T,Ayazgök B,Balkan A,Ozadali-Sari K

    更新日期:2019-05-09 00:00:00

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    pub_type: 杂志文章


    authors: Luo J,Hu Z,Xiao Y,Yang T,Dong C,Huang J,Zhou HB

    更新日期:2017-05-24 00:00:00

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    pub_type: 杂志文章,评审


    authors: Berninger M,Schmidt I,Ponte-Sucre A,Holzgrabe U

    更新日期:2017-07-31 00:00:00

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    pub_type: 杂志文章,评审


    authors: da Silva PN,da Conceição RA,do Couto Maia R,de Castro Barbosa ML

    更新日期:2018-06-06 00:00:00

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    pub_type: 杂志文章


    authors: Zeng F,Qi T,Li C,Li T,Li H,Li S,Zhu L,Xu X

    更新日期:2017-04-26 00:00:00

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    pub_type: 杂志文章


    authors: Sokolova AS,Yarovaya OI,Semenova MD,Shtro AA,Orshanskaya IR,Zarubaev VV,Salakhutdinov NF

    更新日期:2017-03-03 00:00:00

  • Preparation and evaluation of 99mTc-labeled porphyrin complexes prepared using PNP and HYNIC cores: studying the effects of core selection on pharmacokinetics and tumor uptake in a mouse model.

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    pub_type: 杂志文章


    authors: Guleria M,Das T,Vats K,Amirdhanayagam J,Mathur A,Sarma HD,Dash A

    更新日期:2019-02-22 00:00:00

  • High affinity rigidified AT2 receptor ligands with indane scaffolds.

    abstract::Rigidification of the isobutyl side chain of drug-like AT2 receptor agonists and antagonists that are structurally related to the first reported selective AT2 receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >...


    pub_type: 杂志文章


    authors: Wallinder C,Sköld C,Sundholm S,Guimond MO,Yahiaoui S,Lindeberg G,Gallo-Payet N,Hallberg M,Alterman M

    更新日期:2019-11-18 00:00:00

  • Development of selective agents targeting serotonin 5HT1A receptors with subnanomolar activities based on a coumarin core.

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    pub_type: 杂志文章


    authors: Ostrowska K,Grzeszczuk D,Głuch-Lutwin M,Gryboś A,Siwek A,Dobrzycki Ł,Trzaskowski B

    更新日期:2017-07-03 00:00:00

  • On the road to structure-based development of anti-virulence therapeutics targeting the type III secretion system injectisome.

    abstract::The type III secretion system injectisome is a syringe-like multimembrane spanning nanomachine that is essential to the pathogenicity but not viability of many clinically relevant Gram-negative bacteria, such as enteropathogenic Escherichia coli, Salmonella enterica and Pseudomonas aeruginosa. Due to the rise in antib...


    pub_type: 杂志文章,评审


    authors: Lyons BJE,Strynadka NCJ

    更新日期:2019-06-20 00:00:00