ALPHA-SPIROCYCLOPENTYL- AND ALPHA-SPIROCYCLOPROPYL-GAMMA-BUTYROLACTONES - CONFORMATIONALLY CONSTRAINED DERIVATIVES OF ANTICONVULSANT AND CONVULSANT ALPHA,ALPHA-DISUBSTITUTED GAMMA-BUTYROLACTONES

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