Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach.

As part of a program towards the development of novel antibiotics, a convenient method for solid-phase synthesis of the cyclic cationic peptide polymyxin B1 and analogues thereof is described. The methodology, based on cleavage-by-cyclization using Kenner's safety-catch linker, yields crude products with purities ranging from 37-67%. Antibacterial assays revealed that analogues 23-26, in which the (S)-6-methyloctanoic acid moiety is replaced with shorter acyl chains, exhibit distinct antimicrobial activity. The results suggest that the length of the acyl chain is rather critical for antimicrobial activity. On the other hand, substitution of the hydrophobic ring-segment D-Phe-6/Leu-7 in polymyxin B1 with dipeptide mimics (i.e. analogues 27-33) resulted in almost complete loss of antimicrobial activity.     

Effect of benzodiazepines on 5'-nucleotidase activity in rat brain

Experiments on 330 rats were made to study the influence of benzodiazepines (diazepam, dormicum and phenazepam) on 5'-nucleotidase activity in brain homogenates. It was discovered that diazepam and dormicum in doses of 3 and 4 mg, phenazepam in doses of 3.75 and 5 mg per 200 g bw provoked a 16-20% reduction in 5'-nucleotidase activity. The maximal effect of diazepam (3 and 4 mg doses) was attained 1 h after intraperitoneal injection, that of dormicum (3 mg) 30 min and of phenazepam (5 mg) 1 h after intraperitoneal injection. It is assumed that benzodiazepines are involved in AMP metabolism.     

Alterations in cerebrospinal fluid uridine,hypoxanthine, and xanthine in head-injured patients

1. Examination of the cerebrospinal fluid (CSF) of head-injured patients reveals that the concentration of intraventricular xanthine is elevated and that of uridine is decreased relative to those of adult lumbar CSF. 2. No correlations were observed between CSF lactate and CSF hypoxanthine, xanthine, or uridine, suggesting that changes in purine metabolites and the pyrimidine nucleoside do not index similar cellular events as does lactic acid production. 3. Ventricular CSF from hydrocephalic infants had uridine and hypoxanthine concentrations not significantly different from those of normal adult lumbar CSF, but xanthine was significantly elevated. 4. Since uridine has anticonvulsant properties and is a crucial substrate for cerebral metabolism, it may be useful to evaluate this pyrimidine for use in the management of patients with head injury.     

Changes in trace reactions of sensorimotor cortex and putamen neurons as affected by haloperidol

Experiments on conscious rabbits were made to elaborate motor conditioned reflexes through pairing stimuli with electrocutaneous reinforcement applied every 30 s. Neuronal activity in the sensorimotor cortex and putamen was recorded during formation and reproduction of the conditioned reflexes before and after haloperidol injection (0.2 mg/kg i. v.). In the putamen, haloperidol increased the number of neurons exhibiting trace conditioned activity and made the intensity and duration of these processes rise. The changes seen in the sensorimotor cortex were opposite in nature. Inhibition of trace conditioned activity in the sensorimotor cortex depended mainly on the decreased amplitude of the reaction conditioned component. The role of the dopaminergic system in the interaction of the neostriatum and sensorimotor cortex and in formation and reproduction of trace conditioned activity of both the structures is discussed.     

Purine salvage as metabolite and energy saving mechanism in Camelus dromedarius: the recovery of guanine

The preservation of purine ring as purine bases appears to be a common feature of camel liver. Hepatic guanine appears to be actively converted into GMP in the camel rather than further degraded. The limiting step of guanine degradation appears to be the lack of hepatic guanase activity. Higher purine bases over uric acid ratios were found in camel urine with respect to those of zebu.     

Fluorescence technique for comparative studies of substrate-binding subsites in serine proteinases. Application to subtilisins.

A fluorescence technique for comparative studies of substrate-binding subsites in serine proteinases is described. It consists of: selective labelling of the corresponding subsites with a fluorescent group by using N alpha-dansyl(5-dimethylaminonaphthalene-1-sulphonyl)ated peptide chloromethanes containing different numbers of amino acid residues, and probing the immediate environment of the subsites by quenching experiments using ionic and neutral quenchers. Intramolecular distances between the subsites and particular chromophores can be also determined. The technique is of general applicability to all serine proteinases. The above mentioned approach was applied to two proteinases: subtilisin Novo and mesentericopeptidase. It was concluded that the substrate-binding site of mesentericopeptidase is considerably more polar than that of subtilisin Novo. Intramolecular distances between the labelled subsites and tryptophan residues in the two proteinases were determined.