betadex and Angina-Pectoris

Reported here is an analytical method enabling the stereochemical resolution of a new antianginal compound possessing two stereogenic centers, leading to four stereoisomers. Only one of these isomers is currently under development as a novel antianginal agent and consequently, the other three isomers are considered as unwanted chiral impurities. Therefore, an enantioselective method is required in order to check its enantiomeric purity. This paper presents a method exploiting the high efficiency of capillary electrophoresis and the complexing properties of cyclodextrins to achieve the separation of the four stereoisomers of this weakly basic compound (pKa = 7.4). For this purpose, the combination of a neutral cyclodextrin, hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), and an anionic cyclodextrin, carboxymethyl-beta-cyclodextrin (CM-beta-CD), was added to the separation buffer running in an uncoated silica capillary. After selection of the suitable cyclodextrin system, satisfactorily separation conditions were as follows: 30 mM phosphate buffer (pH 6.4) containing 10 mM of HP-gamma-CD and 10 mM of CM-beta-CD, running voltage +30 kV. The resulting run time and resolutions were respectively about 17 min and between 1.95 and 2.84. Linearity curves (0.993 < r2 < 0.998) are also shown.

Topics: Angina Pectoris; beta-Cyclodextrins; Cardiovascular Agents; Electrophoresis, Capillary; gamma-Cyclodextrins; Humans; Molecular Structure; Reproducibility of Results; Stereoisomerism

The vasoinhibitory effect of FR 46171, a new pyridine alcohol derivative, on contractile responses to alpha-adrenoceptor agonists was examined in isolated rabbit aorta. FR 46171 (10(-8)-10(-5) M) inhibited the maximum contractile response to clonidine (CL) in a concentration-dependent manner, but it only inhibited the responses to low concentrations of norepinephrine (NE) and methoxamine (MO). In the aorta pretreated with phenoxybenzamine, however, FR 46171 at 10(-5) M inhibited the residual maximum response to NE and MO. FR 46171 at 10(-5) M only inhibited the response to KCl (20 mM). FR 46171 at 10(-6) and 10(-5) M also moderately inhibited the response to added Ca2+ in a Ca2+-free medium in K+-depolarized preparations. Nifedipine at 10(-6) M, by contrast, nearly abolished the responses to potassium or added Ca2+. In a Ca2+-free medium with EGTA, an addition of NE (10(-5) M), MO (10(-5) M), or CL (10(-5) M) induced a phasic contraction. The inhibitory effect of FR 46171 (10(-8)-10(-5) M) was much greater on the response to CL than that to NE or MO. In a Ca2+-free medium with low EGTA and nifedipine (10(-6) M) in the presence of an alpha-adrenoceptor agonist (NE, MO, or CL), an addition of Ca2+ (2 mM) induced a tonic contraction. FR 46171 (10(-9)-10(-5) M) inhibited the Ca2+ response, which is activated by the agonists, in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Animals; Aorta, Thoracic; beta-Cyclodextrins; Clonidine; Cyclodextrins; Dextrins; Egtazic Acid; In Vitro Techniques; Male; Methoxamine; Muscle, Smooth, Vascular; Nifedipine; Nitroglycerin; Norepinephrine; Phenoxybenzamine; Potassium Chloride; Pyridines; Rabbits; Starch