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.