Evaluation of antiplatelet activity of novel guanidine derivatives in the aspects of their adrenergic receptor activity

Designed acetamide derivatives based on guanidine and various heteroaryl carboxylic acids, were preliminary in vitro study of their adrenergic receptor affinity and anti-plateled effects. The obtained results have showed that exchange of 2,6-dichloro-phenyl substituent of guanidine into heteroaryl moieties, caused the decrease of receptor affinity, especially for α1-adrenoceptors. The observed receptor profile of activity for α2BAR was not changed compared to α1-ARs. Moreover, the observed effects on platelet aggregation induced by sub-threshold concentration of collagen and adrenaline strongly suggested that antiaggregant effect of N- (diaminomethylene)-2-(pyridin-3-yl)acetamide and N-(diaminomethylene)-2-(pyridin-4-yl)acetamide depends on their α2B-ARs antagonistic activity

Chemically homogenous compounds with antagonistic properties at all α1\alpha_{1}-adrenoceptor subtypes but not β1\beta_{1}-adrenoceptor attenuate adrenaline-induced arrhythmia in rats

Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e. α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties.To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 µg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity towards α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A- stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values - it blocked α1A-adrenoceptors around sevenfold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18 and HBK-19 (ED50=0.18-0.21) was comparable to that of carvedilol (ED50=0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18 and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18 and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties.Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e. HBK-16, HBK-17, HBK-18 and HBK-19) were the most compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia

Synthesis of new alpha 2 adrenergic receptor ligands with a potential influence on the metabolism of adipose tissue

We wstępie niniejszej pracy przedstawiono problem otyłości oraz farmakoterapię tego schorzenia. W opisie uwzględniono leki, których stosowanie ma jedynie znaczenie historyczne, leki stosowane obecnie oraz nowe kierunki poszukiwań leków na otyłość, wśród których znaleźli się antagoniści receptora α2-adrenergicznego. Skuteczność antagonistów rec. α2-adrenergicznego w terapii otyłości wydaje się być znacząca, aczkolwiek działania niepożądane związane z ich stosowaniem dyskwalifikują tę grupę leków. Mając na uwadze powyższe oraz fakt, iż wprowadzenie komponenty agonistycznej do cząsteczki antagonisty danego receptora pozwala na zachowanie skuteczności terapeutycznej z jednoczesnym zmniejszeniem działań niepożądanych, zaplanowano otrzymanie związków będących selektywnymi, częściowymi agonistami receptorów α2-adrenergicznych o niskiej aktywności wewnętrznej. W tym celu zaplanowano otrzymanie serii różnie podstawionych, arylopiperazynowych pochodnych układu 4,4-dimetylotetrahydroizochinolino-1,3-dionu, analogów referencyjnego antagonisty receptora α2, związku ARC-239. Aby osiągnąć częściową aktywność wewnętrzną związków, wprowadzono w miejsce podstawnika o-metoksyfenylowego związku AR-C239, różnie podstawione ugrupowania arylowe i heteroarylowe, zdolne do tworzenia wiązań wodorowych z resztami seryny helisy 5, w miejscu wiążącym receptora α2. Postuluje się bowiem, że takie oddziaływania są kluczowym elementem aktywacji receptorów monoaminergicznych. W części chemicznej opisano szczegółową metodologię syntetyczną pochodnych 4,4 dimetylotetrahydro¬izochinolinodionu opartą na trzech analizach retrosyntetycznych. Analiza prowadzonych reakcji pozwoliła również zidentyfikować i opisać powstający produkt uboczny. W wyniku przeprowadzonych prac otrzymano serię 9 nowych związków o potencjalnej aktywności częściowo agonistycznej wobec receptora adrenergicznego α2 oraz referencyjnego antagonistę ARC-239. Struktury otrzymanych pochodnych zostały potwierdzone analizą widm 1H NMR, natomiast ich czystość i jednorodność została sprawdzona za pomocą techniki chromatografii cienkowarstwowej (TLC) oraz chromatografii cieczowej sprzężonej z spektrometrią mas (LC-MS).Uzyskane związki zostały przekazane do farmakologicznych badań in vitro, mających na celu ocenę ich powinowactwa i aktywności wewnętrznej wobec receptorów adrenergicznych typu α2.The worldwide problem of obesity and its pharmacotherapy were discussed in the introduction part. Description was focused on anti-obesity drugs of a historical meaning, currently available treatments as well as novel targets for treating obesity, including α2 adrenergic receptors.Although α2 receptor antagonists seem to be significantly effective in the treatment of obesity they are disqualified as potential anti-obesity drugs because of their serious side effects. Considering the fact, that introduction of some agonist component could allow to maintain therapeutic activity and at the same time decrease possible adverse effects, the synthesis of selective α2 receptor partial agonists, with low intrinsic activity was planned. For that purpose a series of variously substituted arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3-(2H,4H)-dione, analogs of a reference α2 receptor antagonist AR-C239 were designed. In order to achieve compounds with partial agonist activity, o-methoxyphenyl substituent of ARC 239 was replaced with various aryl and heteroaryl moieties, capable of forming hydrogen bonds with the side chains of serine residue at transmembrane helix 5 in the α2 receptor binding site. It is postulated that these interactions are key element of monoaminergic receptors activation.The synthetic methodology of 4,4-dimethylisoquinoline-1,3-(2H,4H)-dione derivatives based on three retrosynthetic analyses was described in the chemical part of the study. Also identification and description of reaction by-product was possible through analysis of synthesis cycle. As a result of conducted reactions the series of nine new chemical compounds with potential partial α2 receptor partial agonist activity as well as a reference antagonist AR-C239 were obtained. Chemical structures of synthesized compounds were confirmed by 1H NMR spectrum analysis, whereas their purity and homogeneity were tested using thin layer chromatography (TLC) and liquid chromatography - mass spectrometry (LC-MS) techniques. Obtained compounds were qualified to pharmacological in vitro studies in order to determine their affinity and intrinsic activity towards α2 receptors

Metabolic and Cardiovascular Benefits and Risks of EMD386088—A 5-HT6 Receptor Partial Agonist and Dopamine Transporter Inhibitor

Since 5-HT(6) receptors play role in controlling feeding and satiety and dopamine is essential for normal feeding behavior, we evaluated the ability of EMD 386088—5-HT(6) receptor partial agonist and dopamine transporter inhibitor—to reduce body weight in obese rats, as well as its anorectic properties (calorie intake reduction) in rat model of excessive eating and the influence on metabolism (plasma glucose and glycerol levels). We also determined the effect of the studied compound on pica behavior in rats and its influence on blood pressure after single administration. EMD 386088 reduced body weight in obese rats fed high-fat diet and decreased calorie intake in both models applied (rat model of obesity and of excessive eating). In both models EMD 386088 regulated plasma glucose and increased plasma glycerol levels. The latter proves that the compound reduced body fat. We think that it might have increased lipolysis, but this requires further studies. The reduction in glucose levels is the first symptom of metabolic disorders compensation. EMD 386088 did not cause pica behavior in rats but increased blood pressure after single administration. We think that partial 5-HT(6) agonists might have potential in the treatment of obesity. Thus, EMD 386088 requires extended studies