ABSTRACT
A series of steroidal compounds were synthesized in order to evaluate the possible influence of the configuration of a stereocenter in the 17beta-side chain on the inhibitory activity on the enzyme 5alpha-reductase (5AR). For this purpose diastereomerically pure 4-azasteroids epimers at C-22 were prepared (compounds 1-11) and tested as inhibitors of 5AR in "in vitro" tests. The obtained data showed that in most cases the couples of epimers possess a significant difference in their biological activity. We also considered, for the tested molecules, a series of chemico-physical parameters in order to find a possible correlation with their biological activity. The findings allowed us to propose a model of the binding site of 5AR which comprises also, for 4-azasteroid inhibitors, the configurational aspect of the 17beta-side chain.
Subject(s)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , 5-alpha Reductase Inhibitors , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Steroids/pharmacology , Animals , Binding Sites/physiology , Drug Design , Isoenzymes/metabolism , Models, Biological , Molecular Conformation , Rats , Steroids/chemical synthesis , Steroids/metabolism , Structure-Activity RelationshipABSTRACT
The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.
Subject(s)
Cerebral Cortex/metabolism , Hippocampus/metabolism , Postpartum Period/metabolism , Pregnancy, Animal/metabolism , Pregnanolone/metabolism , Receptors, GABA-A/metabolism , Animals , Cell Membrane/drug effects , Cell Membrane/metabolism , Chlorides/metabolism , Desoxycorticosterone/analogs & derivatives , Desoxycorticosterone/blood , Estrus/metabolism , Female , Finasteride/pharmacology , Gene Expression Regulation , Muscimol/pharmacology , Pregnancy , Pregnanolone/blood , Progesterone/blood , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/genetics , Time Factors , Transcription, GeneticABSTRACT
A facile method for the synthesis of a series of new steroidal 3-thioxamides from the 3-oxo compound, variously substituted at the 17 position, is described. The "one pot" reaction, using Lawesson's reagent (4-methoxyphenylthionophosphine sulphide dimer) in dichloromethane solution, gives the desired compounds with a high degree of chemoselectivity, in good yields (> 80%).
