New ligands of α2-adrenergic receptor with a potential anti-obesity activity

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Novel candidates for antiobesity drugs

Transcript of New ligands of α2-adrenergic receptor with a potential anti-obesity activity

  • 1. New ligands of 2-adrenergic receptor witha potential anti-obesity activityJoanna niecikowska, Monika Marcinkowska, Adam Bucki, Marcin Koaczkowski, Maciej Pawowski,Agata Siwek, Magdalena Dudek, Jacek SapaFaculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland; obesity is one of the top global health concerns. It is called adisease of civilization of the 21st century.According to the World Health Organization (WHO) 1.4 billion adults areoverweight , and 200 million men and 300 million women are obese.Obesity is suggested to be one of five leading risk factors for globalmortality. Obese subjects are much more at risk for cardiovasculardiseases, gastrointestinal tract diseases and different types of cancer.Nevertheless, the therapeutic efficacy of current drugs remains limitedand obesity present a serious unmet need.Activity of novel tetrahydroisoquinolinedionederivativesGeneral formula of the series targeting 2 receptor is presentedbelow:Although 2 receptor antagonists seem to be significantly effective in thetreatment of obesity their clinical utility as potential anti-obesity drugsbecause of their serious side effects.Considering the fact, that introduction of some agonist component couldallow to maintain therapeutic activity and at the same time decreasepossible adverse effects, the synthesis of selective 2 receptor partialagonists, with low intrinsic activity was planned.AdrenalineAR-C239Synthesis of novel arylpiperazine derivativesof tetrahydroisoquinoline-1,3-dioneGlobal obesity epidemicAdrenaline and AR-C239 (selective 2-adrenergicreceptor antagonist) in 2-adrenergic receptorbinding siteStructures and in vitro data for the tested compounds arecollected in Table 1:AR-C239 does not interact with Ser5.42, therefore showing antagonist properties. Introduction of H-bond forming substituents to the phenyl moiety shouldprovide agonist component to activity of this group of compounds.Compd A R% activity at 2 receptor1.0E-05 M 1.0E-06 M 1.0E-07 M1 79 50 1002 1 51 1003 3 93 1004 1 74 715 1 36 696 4 85 787 17 100 1008 2 24 699 1 51 100AR-C239 1 10 80 The highest activity was observed for compound A8 a 2,2-dimethyl-1,3-benzodioxole derivative (below):We designed and synthesized analogs of a reference 2 receptor antagonistAR-C239, variously substituted at the phenyl ring, to form H-bonds withSer5.42The synthetic methodology of 4,4-dimethylisoquinoline-1,3-(2H,4H)-dionederivatives was based on three retrosynthetic analyses. Adrenaline forms H-bonds with Ser5.42, which contributes to its agonist effect.As a result, synthetic route number II was selected.Synthesis of the series was presented on the example of compound A8Optimization of the synthetic routeNo Conditions% zawarto produktw(A1 /byproduct G) inthe reaction mixture No Conditions% zawarto produktw(A1 /byproduct G) inthe reaction mixture1K2CO3, Et3N,KI, Acetonitrile70C /48h5Et3N, KIDMF100C/48h2Et3N, KIAcetonitrileMicrowave/45min.6K2C O3, K I1,4-dioxane100C / 72h3K2CO3, KIDMF100C/48h7Et3N, KI1,4-dioxane100C/48h4Et3N, KIDMF100C/48h8K2CO3, KI1,4-dioxane50C/24h6040200A1 G42,51%5,56%403020100A1 G31,12%10,01%806040200A1 G77,94%9,02%6040200A1 G59,37%7,15%151050A1 G10,56%3,07%3020100A1 G11.52%24,97%3020100A1 G22,88%8,23%86420A1 G7,28%1,76%AcknowledgementsThe studies were supported by National Centre of Science, grant noDEC-2011/03/B/NZ7/00635 The analysis of conditions used revealed that the end product is formed with thehighest yield using dry 1,4-dioxan in the environment of anhydrous potassiumcarbonate and the presence of a stechiometric amount of potassium iodide at atemperature of 100 C.Based on the in vitro studies, this compound was selected forfurther pharmacological evaluation in animal models of obesity.Asp3.32 Ser5.42Asp3.32 Ser5.42