Subunit-dependent interaction of propoxazepam and its metabolite with the -aminobuturic acid type A receptor

Benzodiazepines (BDZ) are widely used in clinics the treatment of psychiatric disorders, and their main action is considered to be determined by more selective binding with ?1, ?2, ?3 or ?5 subunits GABA receptor.
 The aim this work was studying molecular mechanism new analgesic – propoxazepam its metabolite (3-hydroxypropoxazepam) on ?3, ?4 containing GABAA channels.
 Materials methods ha1b3g2, ha2b3g2, ha3b3g2, ha4b3g2 ha5b3g2 ionotropic GABAARs expressed HEK293 were automated SP384PE Patch Clamp system. In addition, Propoxazepam, 3-hydroxypropoxazepam, diazepam (positive allosteric modulator) control) administered at concentrations 0.001–300 nM determine EC50 Emax for corresponding substances.
 Results ? subunit plays a significantl role determining receptor’s affinity 3-hydroxypropoxazepam. rank order decreasing ?1 = ?5> ?2 > (propoxazepam) ?1> ?2> (3-hydroxypropoxazepam), >?5 (propoxazepam), (3-hydroxypropoxazepam).
 data, transformed Emax/EC50, show that exhibits tenfold (compared diazepam) activity (taking into account magnitude maximum effect) subunit, which distinguishes it from 3-hydroxypropoxazepam.
 Conclusion Due selectivity different subunit-containing GABAA-receptors (mostly types), has potential provide analgesia less sedation than non-selective BDZ.