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Membranes from rat telencephalon contain a single class of strychnine-insensitive glycine sites. That these sites are associated with N-methyl-D-aspartic acid (NMDA) receptors is indicated by the observations that [3H]glycine binding is selectively modulated by NMDA receptor ligands and, conversely, that several amino acids interacting with the glycine sites increase [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the phencyclidine site of the NMDA receptor. The endogenous compound kynurenate and several related quinoline and quinoxaline derivatives inhibit glycine binding with affinities that are much higher than their affinities for glutamate binding sites. In contrast to glycine, kynurenate-type compounds inhibit [3H]TCP binding and thus are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site. These results suggest the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.

Ampakines are drugs structurally derived from aniracetam that potentiate currents mediated by AMPA type glutamate receptors. These drugs slow deactivation and attenuate desensitization of AMPA receptor currents, increase synaptic responses and enhance long-term potentiation. This review focuses mainly on recent physiological studies and on evidence for two distinct subfamilies. Type I compounds like CX546 are very effective in prolonging synaptic responses while type II compounds like CX516 mainly increase response amplitude. Type I and II drugs do not compete in binding assays and thus presumably act through separate sites. Their differences are likely to have consequences also for synaptic plasticity and behavior. Thus, while all ampakines facilitated long-term potentiation, only CX546 enhanced long-term depression. Further discussed are studies showing that ampakine effects vary substantially between neurons, with increases in EPSCs being larger in CA1 pyramidal cells than in thalamus and in hippocampal interneurons. In behavioral tests, ampakines facilitate learning in many paradigms including odor discrimination, spatial mazes, and conditioning, and they improved short-term memory in a non-matching-to-sample task. Positive results were also obtained in various psychological tests with human subjects. The drugs were effective in correcting behaviors in various animal models of schizophrenia and depression. Lastly, evidence is discussed that ampakines have few adverse effects at therapeutically relevant concentrations and that they protect neurons against neurotoxic insults, in part by mobilizing growth factors like BDNF. Type II drugs like CX516 in particular appear to be inherently safe since their ability to prolong responses is kinetically limited.

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R,S-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor up-modulators of the benzamide type ("ampakines") have previously been shown to enhance excitatory synaptic transmission in vivo and in vitro and AMPA receptor currents in excised patches. The present study analyzed the effects of an ampakine (CX614; 2H,3H, 6aH-pyrrolidino[2",1"-3',2']1,3-oxazino[6',5'-5,4]benz o[e]1, 4-dioxan-10-one) that belongs to a benzoxazine subgroup characterized by greater structural rigidity and higher potency. CX614 enhanced the size (amplitude and duration) of field excitatory postsynaptic potentials in hippocampal slices and autaptically evoked excitatory postsynaptic currents in neuronal cultures with EC(50) values of 20 to 40 microM. The compound blocked desensitization (EC(50) = 44 microM) and slowed deactivation of responses to glutamate by a factor of 8.4 in excised patches. Currents through homomeric, recombinant AMPA receptors were enhanced with EC(50) values that did not differ greatly across GluR1-3 flop subunits (19-37 microM) but revealed slightly lower potency at corresponding flip variants. Competition experiments using modulation of [(3)H]fluorowillardiine binding suggested that CX614 and cyclothiazide share a common binding site but cyclothiazide seems to bind to an additional site not recognized by the ampakine. CX614 did not reverse the effect of GYKI 52466 on responses to brief glutamate pulses, which indicates that they act through separate sites, a conclusion that was confirmed in binding experiments. In sum, these results extend prior evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation, and that their effects are exerted through sites that are only in part shared with other modulators.