Flavodilol

Novel enantioselective silica-supported strong and weak cation exchange (SCX and WCX) materials (3.5 μm particles) based on enantiomerically pure N-(4-allyloxy-3,5-dichlorobenzoyl)-2-amino-3,3-dimethylbutanesulfonic acid and corresponding phosphonic acid as well as carboxylic acid structural analogs as chiral selectors have been evaluated for enantiomer separation of chiral bases by non-aqueous capillary electrochromatog. (CEC).Capillary columns packed with these chiral stationary phases (CSPs) showed enantioselectivity in non-aqueous CEC towards a variety of chiral bases including amino alcs. such as β-sympathomimetics and β-blockers.Chromatog. and electrokinetic properties of the strong and weak chiral cation exchangers were evaluated comparatively in terms of their pH^* profile, i.e. in terms of their dependence on the base-to-acid ratio of the background electrolyte.It turned out that the SCX type CSPs, and in particular the one based on the β-amino sulfonic acid show a broader window of applicable and suitable exptl. conditions for CEC.For example, a strong and constant EOF was obtained on the sulfonic acid based CSP over the entire pH^* range studied, while the EOF velocity of the carboxylic acid based CSP was slow under acidic conditions.In the separation of chiral bases, the ion-exchange retention mechanism dominated over electrophoretic migration under most conditions, especially on the SCX type CSPs.The SCX phases exhibited reasonable enantioselectivity over a wider pH^* range, while the weak chiral cation exchanger (WCX type CSP) showed enantiomer separation capabilities for primary, secondary, and tertiary chiral amines only in the alk. pH^* range.Sulfonic and phosphonic acid based CSPs possess broad spectrum of applicability.For example, clenbuterol enantiomers were well baseline resolved both on sulfonic acid based CSP (α = 1.33, R_s = 14.2) as well as phosphonic acid based CSP (α = 1.13, R_s = 4.9).In contrast, under the same conditions the corresponding carboxylic acid CSP exhibited enantioselectivity α of 1.08 and resolution R_s of 1.3 only.

Flavodilol, ((+/-)-7-[2-hydroxy-3-(propylamine)-propoxy]flavone maleate), a new orally effective antihypertensive agent, extensively depleted catecholamines and serotonin in heart tissue of normotensive and spontaneously hypertensive rats (SHR). Dose-response studies demonstrated that greater than or equal to 75% depletion of cardiac norepinephrine (NE) was accompanied by marked blood pressure decline in SHR. In contrast, whole brain biogenic amine levels were decreased only by 15-20% after acute or chronic treatment with antihypertensive doses (35-75 mg/kg). Adrenal epinephrine (EPI) stores were unaffected by acute treatment, although chronic treatment for 18 days with an antihypertensive dose of 75 mg/kg flavodilol decreased EPI by 70%. Acute treatment also decreased serotonin content of spleen by 70-80%. In dogs, a cumulative oral dose of 40 mg/kg decreased catecholamines by greater than or equal to 50% in aorta and heart muscle. Although hypothalamic catecholamine stores appeared to be more susceptible to depletion by flavodilol than catecholamines in other brain regions, these changes did not appear functionally related to blood pressure decreases since analogs of flavodilol without antihypertensive properties produced equivalent or greater depletion of hypothalamic catecholamine stores. In vitro flavodilol promoted spontaneous and potassium-evoked release of dopamine from isolated striatal nerve endings (0.3 microM) and blocked uptake of NE by hypothalamus and hippocampal nerve endings (1 microM), suggesting that biogenic amine depletion in vivo may be caused by an interference with storage and release mechanisms. Despite structural features reminiscent of beta-adrenergic antagonists, flavodilol had low affinity for beta-receptors. Neither was there any inhibition of tyrosine hydroxylase. These findings suggest that the antihypertensive activity of flavodilol results, at least in part, from depletion of sympathetic stores of NE in heart and vascular tissues that moderate adrenergic transmission, thereby decreasing heart rate (HR) and prevailing vascular tone.