Inhibition of [3H]GABA binding to rat brain synaptic membranes by bicuculline related alkaloids.

The binding of 45 bicuculline related phthalideisoquinoline alkaloids to the GABAA receptor was studied using rat brain synaptic membranes prepared both in Tris-HCl and in Tyrode buffers. The IC50 values determined in Tyrode for phthalideisoquinolines are lower (by about one order of magnitude) than and correlate well (r2 = 0.95) with the IC50 data obtained by [3H]GABA displacement in Tris-HCl. Applying Tyrode, the activities of GABA agonists relative to Tris-HCl are decreased. It can be recognized that activities in receptor binding are dependent on the conformations phthalideisoquinolines prefer in solution. On the basis of systematic alterations in the phthalideisoquinoline molecule the main structural elements involved in the binding of phthalideisoquinoline alkaloids appear to be identical with those of GABA agonists, suggesting that the same binding conformation of the GABAA receptor may be implicated for both agonists and antagonists. The opposite shift in relative potencies of agonists and antagonists may be the consequence of an alteration in the "ionic status" rather than that in the conformation of the GABAA receptor.