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Filipić Slavica
03/2013Dissertation
Earlier pharmacological studies allowed characterization of the three main imidazoline receptors classes: I1-, I2- and I3-IR. Activation of both I1-imidazoline receptors and α2-adrenergic receptors (α2-AR) is responsible for central sympathoinhibitory action and lowering of the blood pressure. Compounds such as moxonidine and rilmenidine are more selective for I1-imidazoline receptors and have produced less side effects than clonidine and other nonselective imidazoline receptors ligands. In the framework of this doctoral dissertation, quantitative structure activity/selectivity relationships of imidazoline and α2-adrenergic receptors ligands, as well as quantitative structure retention/mobility relationships of these compounds in the reversed-phase high performance liquid chromatography (RP-HPLC) and in capillary electrophoresis (CE) were performed. Appropriate mathematical models able to predict biological activity and retention/mobility of newly synthesized compounds, potential ligands of imidazoline and α2-adrenergic receptors were developed. QSAR (Quantitative Structure Activity Relationship) analysis was used to define molecular parameters responsible for a high I1-receptors binding affinity and high I1/α2-selectivity. The theoretical approach indicates that an increase in lipophilicity (logD7,4) and molar refractivity together with a decrease in an average N-charge in the heterocyclic moiety are responsible for a better binding affinity of an active site in the I1-receptors, whereas lipophilicity (logP) and HOMO energy are the important descriptors of the I1/α2-selectivity. Optimization of the experimental conditions for a rapid and efficient separation of 11 imidazoline and α2-adrenergic receptors ligands was performed by capillary electrophoresis. An influence of the buffer pH and concentration, temperature, voltage and various concentrations of α-, β- and γ-cyclodextrins (CD) on the electrophoretic mobility and resolution of compounds in the mixture has been examined. At the beginning of this theoretical study and in order to generate information about interactions occurring between analytes and cyclodextrins in the given CE systems, complexation of ligands with α-, β-, and γ-CD was examined by a semi-empirical PM3 method. Linear and nonlinear methodologies have been applied to building the QSMR (Quantitative Structure Mobility Relationship) models, with an aim to define quantitative relationships between the chemical structure and the electrophoretic mobility of the investigated compounds in the presence of α-, β- and γ-cyclodextrin. Optimal QSMR models revealed an important role of the ligand-CD complex descriptors in predicting the migration behavior of the analyzed compounds in the given CE systems. At an initial step of the development of the CE method, the proposed multi-target QSMR model can be used as a fast screening model for an assessment of the migration time of the related antihypertensives in the presence of three different cyclodextrins, and for selection of the best cyclodextrin for the separation of the analyzed compounds. An impact of the ionization degree (under the acidic, neutral and basic conditions) of imidazoline and a-adrenergic receptors ligands on the retention in the reversed-phase liquid chromatography and on mobility in capillary electrophoresis has been examined. The most significant molecular descriptors in the selected QSRR {Quantitative Structure Retention Relationship) models pointed out that an important knowledge concerning the retention behaviour can be derived from the 0D-, 1D- and 2D-descriptors, which provide an information about chemical composition of the compounds, their molecular properties (lipophilicity), and molecular branching. On the other hand, a reliable prediction of electrophoretic mobility can be performed by calculating the appropriate 2D- and 3D-descriptors, which provide an information on molecular size and complexity, and also on the influence of the charge transfer and the electronic properties on the migration behaviour. Correlations between the retention parameters obtained by the RP-HPLC technique at the three different pH values (4,4; 7,4 and 9,1) and the calculated lipophilicity parameters (logD4,4, logD7,4 and logD9,1) were examined. The presented approach can be applied for preliminary assessment of lipophilic properties of the related compounds. Capillary electrophoresis was applied to determine the acid-base ionization constants of 10 imidazoline and α2-adrenergic receptors ligands. On the basis of the results obtained, it is possible to accurately determine the degree of drug ionization at the different physiological and analytical pH values. Na osnovu farmakoloških studija do danas je izvršena karakterizacija tri osnovne klase imidazolinskih receptora: I1-, I2- i I3-IR. Aktivacija I1-imidazolinskih i α2-adrenergičkih receptora (α2-AR) je odgovorna za centralnu inhibiciju simpatikusa i sniženje krvnog pritiska. Jedinjenja sa većom selektivnošću za I1-receptore, kao što su moksonidin i rilmenidin, pokazala su manji stepen neželjenih efekata koji nastaju aktivacijom (α2-adrenergičkih receptora. U ovoj doktorskoj disertaciji izvršeno je ispitivanje kvantitativnih odnosa strukture, aktivnosti i selektivnosti liganada imidazolinskih i α2-adrenergičkih receptora, kao i ispitivanje kvantitativnih odnosa strukture i retencije/pokretljivosti ovih jedinjenja u reverzno-faznoj tečnoj hromatografiji i kapilarnoj elektroforezi (CE). Formirani su odgovarajući matematički modeli na osnovu kojih je moguće izvršiti predviđanje biološke aktivnosti i retencije/pokretljivosti novih jedinjenja, potencijalnih liganada imidazolinskih i α2-adrenergičkih receptora. QSAR (Quantitative Structure Activity Relationship) analizom su definisani molekulski parametri odgovorni za postizanje visokog afiniteta vezivanja jedinjenja za I1-imidazolinske receptore kao i za postizanje I1/α2-selektivnosti. Dobijeni rezultati su ukazali da porast lipofilnosti (logD7,4) i molarne refraktivnosti, zajedno sa smanjenjem naelektrisanja na atomima azota heterociklusa dovodi do snažnijeg afiniteta ka I1-IR, dok su lipofilnost (logP) i HOMO energija važni deskriptori I1/α2-selektivnosti. Izvršena je optimizacija eksperimentalnih uslova za brzo i efikasno razdvajanje smeše 11 imidazolinskih i α2-adrenergičkih liganada metodom kapilame elektroforeze. Ispitan je uticaj koncentracije i pH vrednosti pufera, temperature, napona i različitih koncentracija α-, β- i γ-ciklodekstrina (CD) na elektroforetsku pokretljivost i rezoluciju jedinjenja u smeši. Na početku teorijske studije, sa ciljem da se dobiju informacije 0 interakcijama između analita i ciklodekstrina u datim elektroforetskim sistemima, kompleksiranje analiziranih liganada sa α-, β- i γ-CD je ispitano semi-empirijskim PM3 metodom. Primenom linearnih i nelinearnih statističkih metoda formirani su QSMR {Quantitative Structure Mobility Relationship) modeli kojima su defmisani kvantitativni odnosi između hemijske strukture i elektroforetske pokretljivosti jedinjenja u prisustvu α-, β- i γ-CD. Formirani QSMR modeli ukazali su na važnu ulogu deskriptora ligand-ciklodekstrin kompleksa u predviđanju migracionog ponašanja ispitivanih jedinjenja u datom elektroforetskom sistemu. Predložen je i multi-target QSMR model koji može biti korišćen u inicijalnoj fazi razvoja metode kao brz screening model za procenu migracionog vremena srodnih antihipertenziva u prisustvu α-, β- i γ-CD i za odabir optimalnog ciklodekstrina kojim se postiže razdvajanje analiziranih jedinjenja. Ispitan je uticaj stepena jonizacije (kisele, neutralne i bazne sredine) liganada imidazolinskih i α-adrenergičkih receptora na retenciju u reverzno-faznoj tečnoj hromatografiji pod visokim pritiskom (RP-HPLC) i pokretljivost u kapilarnoj elektroforezi. Najznačajniji molekulski deskriptori u formiranim QSRR (Quantitative Structure Retention Relationship) modelima ukazali su da se važni podaci o retencionom ponašanju mogu dobiti na osnovu OD-, 1D- i 2D-deskriptora koji nose informacije o hemijskom sastavu jedinjenja, molekulskim osobinama (lipofilnosti) i račvanju molekule. Sa druge strane, pouzdano predviđanje elektroforetske pokretljivosti može se izvršiti računanjem odgovarajućih 2D- i 3D-deskriptora od kojih većina daje informacije o molekulskoj veličini i kompleksnosti, kao i o uticaju naelektrisanja i elektronskih osobina na migraciono ponašanje. Ispitana je korelacija retencionih parametara određenih RP-HPLC metodom pri tri različite pH vrednosti (4,4; 7,4 i 9,1) sa teorijski izračunatim parametrima lipofilnosti (logD4,4, logD7,4 i logD9,1). Dobijeni rezultati su ukazali da se ovaj pristup može primeniti za preliminamu procenu lipofilnih karakteristika srodnih jedinjenja. Metodom kapilame elektroforeze određene su kiselinsko-bazne konstante jonizacije 10 liganada imidazolinskih i α2-adrenergičkih receptora na osnovu kojih je moguće precizno odrediti stepen jonizacije leka pri različitim fiziološkim i analitičkim pH vrednostima.
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