BINDING OF THE NEW RADIOLIGAND (S)-[H-3]AMPA TO RAT-BRAIN SYNAPTIC-MEMBRANES - EFFECTS OF A SERIES OF STRUCTURAL ANALOGS OF THE NON-NMDA RECEPTOR AGONIST WILLARDIINE

This study examined the binding of (S)[H-3]AMPA, the radiolabelled act ive isomer of AMPA, to rat brain synaptic membranes. Under non-chaotro pic conditions specific binding of 10 nM (S)-[H-3]AMPA represented 33 +/- 2% of the total; this increased to 74 +/- 1% in the presence of 10 0 mM KSCN. (S)-[H-3]AMPA binding was inhibited by non-NMDA receptor ag onists and the antagonists NBQX and CNQX, with the following rank orde r of potency: NBQX > (S)-AMPA greater than or equal to quisqualate > C NQX > L-glutamate > domoate greater than or equal to kainate > (R)-AMP A. NMDA, and the metabotropic glutamate receptor agonist (1S,3R)-ACPD, up to 100 mu M, did not inhibit (S)-[H-3]AMPA. binding. A number of w illardiine analogues all effectively inhibited (S)-[H-3]AMPA binding w ith the rank order of potency: (S)-5-fluorowillardiine > (S)-5-nitrowi llardiine > (S)-5-trifluoromethylwillardiine > (S)-5-bromowillardiine approximate to (S)-5-chlorowillardiine > (S)-5-cyanowillardiine > (S)- willardiine > (S)-5-iodowillardiine > (S)6-methylwillardiine > (S)-5-m ethylwillardiine. This rank order closely reflects data from equilibri um measurements made, under voltage clamp, on cultured hippocampal neu rons. In contrast the respective (R)-enantiomers and the racemate mixt ures of (R,S)-3, 5 and 6-isowillardiine were relatively inactive. Simi lar IC50 values and thus rank orders of potency for the willardiines w ere observed in the presence of 100 mM KSCN.