ABSTRACT
The dissociation constants of new 2-amino-2-oxazolines were determined by capillary electrophoresis (CE) as a new technique. A method based on a linear model has been used in the CE determination. A series of eight 2-amino-2-oxazolines are investigated to determine their ionization constant. Among them, three new oxazolines synthesized are presented. The Ka values were obtained from the plots of reciprocal effective mobility against inverse concentrations of protons. The potentiometric method (PM) was performed as a comparative method. No significant differences were observed between the determined dissociation constants using both methods. Thus, the pKa values have been found to vary between 8.55 and 8.68.
Subject(s)
Electrophoresis, Capillary/methods , Oxazoles/analysis , Buffers , Hydrogen-Ion Concentration , Magnetic Resonance SpectroscopyABSTRACT
PAF is a potent lipid mediator involved in many pathological disorders, such as platelet aggregation, immuno-inflammatory reactions, vascular disorders, septic shock and bronchoconstriction. We chose to study the electronic and lipophilic properties of eleven PAF antagonists, comprising five tetrahydrofuran derivatives, four hetrazepines, the ginkgolide BN-52021 and the pyrrolo-thiazole derivative RP-59227. A Molecular Electrostatic Potential (MEP) contour drawn at -25 kCal/Mol shows three electronegative areas in most compounds. Two areas can be considered as analogous to those described in the so-called "Cache-Oreille" (Earmuff) Model. Molecular Lipophilicity Potential (MLP) analysis allows us to characterise one hydrophilic area, localised at the same place as one of the electronegative areas, and two lipophilic areas, of which the biggest draws a typical "sock" contour. These three areas represent the minimal requirements for a high affinity to the PAF receptor. MEP and MLP results are here combined to propose a pharmacophore for PAF antagonists, including two lipophilic areas, two hydrophilic and electronegative areas and an electronegative zone with no particular hydrophilic behaviour.
Subject(s)
Azepines/chemistry , Furans/chemistry , Platelet Activating Factor/antagonists & inhibitors , Receptors, Cell Surface , Receptors, G-Protein-Coupled , Animals , Azepines/pharmacology , Chemical Phenomena , Chemistry, Pharmaceutical , Chemistry, Physical , Electrochemistry , Furans/pharmacology , Humans , Molecular Conformation , Platelet Membrane Glycoproteins/antagonists & inhibitorsABSTRACT
This paper proposes a new tool that allows us to see the following in the same frame: (1) 3D geometrical features of a molecule, and (2) pseudo-3D representation of the lipophilicity molecular potential. It thus becomes very easy to compare the lipophilicity molecular potential gradient of different molecules having the same pharmacological properties. An example of two structurally dissimilar anti-PAF molecules is given.
Subject(s)
Computer Graphics , Diterpenes , Lignans , Models, Molecular , Benzofurans/chemistry , Fats , Ginkgolides , Lactones/chemistry , Mathematics , SolubilityABSTRACT
This paper describes a kinetic comparative study of plasma concentrations of isosorbide dinitrate (ISDN) and its mononitrate derivatives (2-ISMN or 5-ISMN) after oral administration of a sustained release form of ISDN or a (non) sustained release form of 5-ISMN. The blood extracts determinations were performed by electron capture gas chromatography which is an accurate and sensitive method suitable for the quantitation of concentrations in the nanogram per ml range. The results are in good agreement with those of the literature. The standard form of 5-ISMN is rapidly absorbed. The Tmax value is approximately 1H with a corresponding Cmax value close to 400 ng/ml. For the sustained release drugs, the Tmax increases to 6H and Cmax is nearly half the 5-ISMN standard form value. Considering the administered dose, it seems better to use 5-ISMN than ISDN. For a long lasting treatment of angina pectoris and ischaemic cardiac diseases, both forms can be used.
