Lajos Gruber

Common modes of action of γ-butyrolactones and pentylenetetrazol on the GABAA receptor-ionophore complex

The effects of pentylenetetrazol and bicyclic gamma-butyrolactones of similar stereostructures were studied on the convulsant and benzodiazepine binding sites and chloride ionophore activity of the gamma-aminobutyric acid (GABAA) receptor-complex. Bicyclic gamma-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [35S]t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyclic gamma-butyrolactones decreased their IC50 values by one order of magnitude. The IC50 values of saturated bicyclic gamma-butyrolactones and pentylenetetrazol were increased by GABA versus its antagonist R 5135 (3 alpha-hydroxy-16-imino-5 beta,17-aza-androstan-11-one). A bicyclic gamma-butyrolactone and pentylenetetrazol accelerated the dissociation of [35S]TBPS, displaced [3H]flumazenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cortical neurones in culture in a similar manner. These similar effects on binding and ionophore function support their common modes of action on the GABAA receptor-ionophore complex.

Synthetic studies towards (−)-carba-3′-deoxy-3′-fluorothymidine.

Abstract Stereospecific synthesis of (−)-carba-3′-deoxy-3′-fluorothymidine (−)- 11 is reported from the protected (−)-carbocyclic 3′-epi-thymidine (−)- 7 using diethylaminosulfur trifluoride. Under the conditions used, extensive dehydration of the blocked precursor into 10 and formation of the 4′-fluoro analogue ( 9 ) were also observed. An attempted simplification of our methodology based on (+)-(1R, 5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one failed, but a novel cyclopentane ( 2 ) ring expansion to tetrahydropyran ( 18 ) was discovered.

Prins reaction of 2-oxabicyclo[3.3.0]oct-6-en-3-one and related derivatives

Abstract Reaction of formaldehyde with the title olefinic lactone in acetic acid affords diacetate of 1,3-diol ( 2a ) as the main product in 50 – 60% yield via regioselective trans-addition. Less favourable results were obtained with related bicyclic derivatives.

Hydride shift in the solvolysis of 5-substituted PGi1 derivatives

Abstract Silver ion mediated solvolysis of 5-iodo-PGI 1 derivatives as well as the reaction of PGF 2α methylester with thallium triacetate in acetic acid were studied with the aid of deuterium isotope labelling. In protic solvents (methanol, acetic acid) high retention (70–90%) of the deuterium label is compatible with a vicinal hydride shift whereas in non-protic solvents (e.g. pyridine) elimination occurs.