[H-3] L-655,708, A NOVEL LIGAND SELECTIVE FOR THE BENZODIAZEPINE SITEOF GABA(A) RECEPTORS WHICH CONTAIN THE ALPHA-5 SUBUNIT

A compound (L-655,708) has been identified which has at least 50-fold selectivity for the benzodiazepine site on GABA(A) receptors containin g an alpha 5 subunit over those containing an alpha 1, alpha 2, alpha 3 or alpha 6 subunit in combination with beta 3 and gamma 2. The compo und was radiolabelled with tritium and investigated as a novel radioli gand which recognizes the benzodiazepine site of GABA(A) receptors whi ch contain the alpha 5 subunit. [H-3]L-655,708 labels one saturable an d specific population of binding sites in rat hippocampus with a K-d o f 2.4 +/- 0.7 nM and a B-max of 256 +/- 42 fmol/mg protein. The pharma cology of the binding site labelled was consistent with that of recept ors present in cells transfected with alpha 5, beta 2 and gamma 2 and with receptors immunoprecipitated from rat brain with an alpha 5-selec tive antiserum. It is concluded that [H-3]L-655,708 is the first radio ligand to date which is selective for any BZ2 subtype of the GABA(A) r eceptor and should provide a valuable tool for elucidating the structu re and function of the alpha 5-containing GABA(A) receptor subtype. Co pyright (C) 1996 Elsevier Science Ltd.