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GABA A receptors (GABA A Rs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). Previously, using photoreactive analogs of etomidate ([ 3 H]azietomidate) and mephobarbital [[ 3 H]1-methyl-5-allyl-5-( m -trifluoromethyl-diazirynylphenyl)barbituric acid ([ 3 H] R - m TFD-MPAB)], we identified two homologous but pharmacologically distinct classes of general anesthetic binding sites in the α 1 β 3 γ 2 GABA A R transmembrane domain at β  + - α  - ( β  + sites) and α  + - β  - / γ  + - β  - ( β  - sites) subunit interfaces. We now use competition photolabeling with [ 3 H]azietomidate and [ 3 H] R-m TFD-MPAB to identify para -substituted propofol analogs and other drugs that bind selectively to intersubunit anesthetic sites. Propofol and 4-chloro-propofol bind with 5-fold selectivity to β  + , while derivatives with bulkier lipophilic substitutions [4-( tert -butyl)-propofol and 4-(hydroxyl(phenyl)methyl)-propofol] bind with ∼10-fold higher affinity to β  - sites. Similar to R-m TFD-MPAB and propofol, these drugs bind in the presence of GABA with similar affinity to the α  + - β  - and γ  + - β  - sites. However, we discovered four compounds that bind with different affinities to the two β  - interface sites. Two of these bind with higher affinity to one of the β  - sites than to the β  + sites. We deduce that 4-benzoyl-propofol binds with &gt;100-fold higher affinity to the γ  + - β  - site than to the α  + - β  - or β  + - α  - sites, whereas loreclezole, an anticonvulsant, binds with 5- and 100-fold higher affinity to the α  + - β  - site than to the β  + and γ  + - β  - sites. These studies provide a first identification of PAMs that bind selectively to a single intersubunit site in the GABA A R transmembrane domain, a property that may facilitate the development of subtype selective GABA A R PAMs.

molecular pharmacology

Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the α1β3γ2 GABAAR Transmembrane Domain