[H-3]L-655,708, A Novel Ligand Selective For The Benzodiazepine Site Of 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 containing 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 compound was radiolabelled with tritium and investigated as a novel radioligand which recognizes the benzodiazepine site of GABA(A) receptors which contain the alpha 5 subunit. [H-3]L-655,708 labels one saturable and specific population of binding sites in rat hippocampus with a K-d of 2.4 +/- 0.7 nM and a B-max of 256 +/- 42 fmol/mg protein. The pharmacology of the binding site labelled was consistent with that of receptors present in cells transfected with alpha 5, beta 2 and gamma 2 and with receptors immunoprecipitated from rat brain with an alpha 5-selective antiserum. It is concluded that [H-3]L-655,708 is the first radioligand to date which is selective for any BZ2 subtype of the GABA(A) receptor and should provide a valuable tool for elucidating the structure and function of the alpha 5-containing GABA(A) receptor subtype. Copyright (C) 1996 Elsevier Science Ltd.