Studies on Propafenone-type Modulators of Multidrug-Resistance IV: Synthesis and Pharmacological Activity of 5-Hydroxy and 5-Benzyloxy Derivatives

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC₅₀ values, independent of their log P value.     

Inborn errors of the urea cycle

Inborn errors of the urea cycle are an important cause of hyperammonaemia throughout childhood, and are associated with high morbidity and mortality rates. If they are diagnosed early and treated appropriately, the outcome for affected children is significantly improved.     

Gastric emptying and anaesthesia

An understanding of factors which influence gastric emptying rate is important for anaesthetists. In the absence of pyloric stenosis or other mechanical obstruction to the gastric outlet, opioid drugs constitute the most important cause of delayed emptying in the perioperative period.     

Subfractionation of human peripheral blood lymphocytes by partitioning in two-polymer aqueous phase systems. Characteristics of a small subpopulation of cells with high partition coefficient

Mixtures of aqueous solutions of dextran and poly(ethylene glycol) form immiscible 2-phase systems that are suitable for the separation of viable, functionally-competent cells on the basis of their surface properties. With the appropriate choice of ionic composition, these systems will separate cells on the basis of charge-related surface characteristics. We have previously shown that in charge-sensitive phase systems, human B lymphocytes have a low partition coefficient (K) and T cells have an intermediate K. The cell subpopulation with the highest K values contains large null lymphocytes that have most of the antibody-dependent and natural killer activities. The present study further characterizes this latter cell subpopulation. 8-33% of peripheral blood lymphocytes in normal persons had high K values. About 50% of these cells had typical Giemsa-staining granules characteristic of killer cells and one third had Fc receptors, but lacked complement receptors. Although 15-30% of the cells with high K values formed rosettes with sheep erythrocytes, there was virtually no response to T-cell mitogens such as PHA and Con A. Mixing cells having high K values with mitogen-responsive T cells from intermediate cell fractions revealed no evidence of suppressor-cell activity to explain the poor mitogen response. The studies indicate that a heterogeneous population of cells share charge-related surface properties resulting in a high partition coefficient. These cells comprise a significant proportion of human peripheral blood lymphocytes and include virtually all of the large granular lymphocytes as well as a large population without this morphology that shares the feature of unresponsiveness to T-cell mitogens.