Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked allosterically to benzodiazepine receptors.
The interactions of zopiclone and suriclone, representatives of nonbenzodiazepine cyclopyrrolone anxiolytics, with central-type benzodiazepine receptors have been characterized in rat and bovine brain. While zopiclone potently (IC50 approximately 50 nM) inhibits [3H]Ro-15-1788 binding in an apparent mass action fashion, suriclone and its metabolite 35,489 RP are extremely potent (IC50 approximately 350 pM and 1 nM, respectively) and display Hill coefficients of approximately 2.0. Like classical benzodiazepines, none of the cyclopyrrolones studied display selectivity for type I or type II benzodiazepine receptors. Using [3H]suriclone, saturable high affinity sites for cyclopyrrolone anxiolytics were directly labeled in rat and bovine brain. The regional distribution and pharmacologic specificity of [3H]suriclone and [3H]Ro-15-1788 binding sites are similar, suggesting that [3H]suriclone recognition sites reside on the benzodiazepine receptor complex. Unlike classical benzodiazepine agonists, such as diazepam, the binding of [3H]suriclone is not modulated by GABA, Cl-, pentobartibal, or tracazolate. Unlike those of [3H]diazepam, [3H]suriclone-binding sites are only minimally affected by photoaffinity labeling with flunitrazepam. Whereas the binding affinities of [3H]Ro-15-1788, [3H]flunitrazepam, and [3H]ethyl beta-carboline 3-carboxylate increase at lower temperatures, [3H]suriclone binds with higher affinity at higher temperatures. Scatchard analysis of [3H]flunitrazepam, [3H]ethyl beta-carboline 3-carboxylate, and [3H]Ro-15-1788 binding in the presence of all cyclopyrrolones studied reveals an apparent noncompetitive pattern of inhibition of binding in each case; by contrast, inhibition of [3H]suriclone binding by Ro-15-1788 flunitrazepam, methyl beta-carboline 3-carboxylate and all of the cyclopyrrolones studied appears competitive. The dissociation kinetics of [3H]Ro-15-1788 indicate that cyclopyrrolones, but not benzodiazepines, increase the dissociation rate of [3H]Ro-15-1788 from its membrane receptors; the converse is true for [3H]suriclone dissociation kinetics. The association kinetics of [3H]suriclone suggest that suriclone induces a conformational change upon binding to receptors. Taken together, these results indicate that [3H]suriclone labels a site on the benzodiazepine receptor complex allosteric to the recognition site for benzodiazepines. A model is proposed to describe the interaction between benzodiazepines and cyclopyrrolones.
D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D053961:Azabicyclo Compounds; D001569:Benzodiazepines / Q000378:metabolism*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008433:Mathematics; D009287:Naphthyridines; D010879:Piperazines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D013457:Sulfur Compounds; D014018:Tissue Distribution
D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D009287:Naphthyridines; D010879:Piperazines; D011963:Receptors, GABA-A; D013457:Sulfur Compounds; C515050:zopiclone; D001569:Benzodiazepines; C037283:suriclone