Docking of 1,4-Benzodiazepines in the 1/2 GABAA Receptor Modulator Site□S

Positive allosteric modulation of the GABAA receptor (GABAAR) via the benzodiazepine recognition site is the mechanism whereby diverse chemical classes of therapeutic agents act to reduce anxiety, induce and maintain sleep, reduce seizures, and induce conscious sedation. The binding of such therapeu-tic agents to this allosteric modulatory site increases the affinity of GABA for the agonist recognition site. A major unanswered question, however, relates to how positive allosteric modula-tors dock in the 1,4-benzodiazepine (BZD) recognition site. In the present study, the X-ray structure of an acetylcholine bind-ing protein from the snail Lymnea stagnalis and the results from site-directed affinity-labeling studies were used as the basis for modeling of the BZD binding pocket at the 1/2 subunit inter-face. A tethered BZD was introduced into the binding pocket