Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant alpha,alpha-disubstituted gamma-butyrolactones.

摘要: To further study the putative gamma-butyrolactone site of GABAA/chloride channel complex, constrained derivatives convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized evaluated biologically. Most spirocyclopropyl agents anticonvulsants when tested against pentylenetetrazole-induced seizures in mice. These effectively displaced 35[S]-tert-butylbicyclophosphorothionate (35[S]-TBPS), a ligand for picrotoxin binding channel, from rat neuronal membranes affected GABA-mediated current hippocampal neurons. The monomethyl-substituted agent with methyl group cis to carbonyl (15) potentiates GABA-induced whereas trans derivative (16) blocks current. only spirocyclopentyl series was unsubstituted compound 2. All other substituted targets inactive vivo at highest dose except 9, which has 2,5-dimethyl-substituted cyclopentyl ring. 35[S]-TBPS very effectively, they also all potentiated chloride 9 blocked From data obtained this investigation, it appears that volume occupied above below lactone ring is as large by activity observed. Groups less these areas either are behavioral test or have activity. When bound larger molecules may stabilize closed state smaller open state.