Hippocampal CAl pyramidal cell neurons are sensitized over 30-fold to depolarization by l-2- amino-4-phosphonobutanoic acid (l-AP4) following exposure to l-quisqualic acid. This phenomenon has been termed the QUIS effect. In the present study several novel l-quisqualic acid analogues have been synthesized and tested for their interaction with the different components of the QUIS effect system. Replacement of the oxadiazolidinedione ring of l-quisqualic acid with several other types of heterocyclic rings yielded the following quisqualic acid analogues: maleimide 2, N-methylmaleimide 3, N-(carboxymethyl)maleimide 4, succinimides 5A and 5B, and imidazolidinedione 6. None of these analogues were able to mimic the effects of l-quisqualic acid and sensitize hippocampal CAl neurons to depolarization by l-AP4. Also, unlike l-serine O-sulfate, l-homocysteinesulfinic acid, or l-α-aminoadipic acid, none of the analogues were able to preblock or reverse the QUIS effect. However, when the IC50 values for inhibition of the CAl synaptic field potential of analogues 2-6 were determined both before and after hippocampal slices were exposed to l-quisqualic acid, the IC50 values of analogues 3 and 4 were found to decrease more than 7-fold. Thus, these two compounds behave like l-AP4 rather than l-quisqualic acid in this system in that they exhibit increased potencies in slices that have been pretreated with l-quisqualic acid even though they cannot themselves induce this sensitization. Compounds 3 and 4, therefore, represent the first non-phosphorus-containing compounds to which hippocampal neurons become sensitized following exposure to l-quisqualic acid. No change in the IC50 values was observed for 5A or SB. Analogues 2 and 6, on the other hand, displayed a high potency for inhibition of the evoked field potential even prior to treatment of the slices with l-quisqualic acid.