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.     

Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: A hypothesis on the molecular mechanism of the OTC deficiency

Mutations P225L and P225R were identified in codon 225 of the gene for ornithine transcarbamylase (OTC) in two patients with the neonatal form of OTC deficiency. The mutations occur at a CpG dinucleotide and eliminate a unique MspI restriction site in exon 7 of the OTC gene. They do not alter existing splice sites or create new sites, as judged from the nucleotide sequence. Both mutations are associated with undetectable levels of OTC antigen in liver homogenates, and with either complete lack of OTC activity (P225R mutation) or very small residual activity (0.15% of normal in the P225L mutation). The residual activity observed with P225L exhibits normal pH dependence, little or no increases in the Km values for ornithine and carbamoyl phosphate and normal stability at either 37°C or, in the presence of 0.66 mol/L urea, at 0°C. The latter conditions were used to examine whether the P225L mutation favours dissociation of the active OTC trimer. Given the normal stability and lack of tendency to dissociation of the mutant enzyme, it appears likely that the dramatic reduction in the level of OTC protein is due to inefficient conversion of the mutant OTC precursor polypeptide (pOTC) into the correctly localized, appropriately folded, mature enzyme trimer, suggesting degradation of pOTC in transit to the mitochondria.     

Disposition of [3H]flobufen and its active metabolite in rats

The present authors investigated the excretion, distribution and pharmacokinetics of the novel potential antirheumatic agent flobufen and its active metabolite after p.o. and i.v. doses of 2, 10 and 50 mg/kg administered to rats. The drug is resorbed well from the digestive tract and mostly it is metabolized to the principal metabolite M, which is only slowly excreted from the organism mainly by renal clearance. Within the whole dose range the kinetics of the drug is linear. Binding of flobufen and M to proteins is high (95-99%). The highest concentrations of radioactive metabolites (mostly M) were found in the plasma, liver, lungs, kidneys, connective tissue and inflammatory foci. The penetration of metabolites through the placenta and excretion in human milk are relatively important.     

Melatonin modifies the spontaneous multiunit activity recorded in several brain nuclei of freely behaving rats.

Melatonin, a pineal hormone, released photoperiodically, was administered systemically in rats, previously implanted with semimicroelectrodes into six different brain structures. The multiunit electrical activity of these structures was recorded for 10 min before and 60 min after melatonin administration in unanesthetized, freely moving rats. Different melatonin doses (100, 200, 500, and 1000 micrograms/kg) produced changes in the electrical activity of all tested structures. However, amygdala, rostral hypothalamus and mesencephalic reticular formation showed the most important changes. The main effect induced by melatonin was a dose-related decrease of the spontaneous electrical activity. The significance of these effects is discussed within the context of the behavioral and endocrinological effects of melatonin.     

Long-lasting effects of chronic chlorimipramine treatment of rats on exploratory activity on a hole-board, and on immobility in the forced swimming test

The study concerned the effects of acute and chronic clomipramine administration to male rats on exploratory activity in a novel environment (hole-board) and on immobility in the forced swimming test. Acute clomipramine administration did not alter either exploratory activity on a hole-board as measured 3 or 20 h after drug administration, or immobility in the forced swimming test as measured 20 h after drug administration. Approximately 20 h after the last injection of clomipramine, the rats chronically treated with the drug showed reduced exploratory activity on the hole-board. In contrast, chronic clomipramine treatment significantly increased the activity in the forced swimming test. The effects of the drug on exploratory and forced swimming activities persisted for 14 days after the cessation of clomipramine administration. These data indicate that chronic clomipramine administration exerted profound and long-lasting effects on central nervous system function. The long-lasting action of the drug on behaviour in the forced swimming test might explain the long-term beneficial effect of antidepressant drugs in counteracting behavioral depression.