CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [³H]acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA₂ = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [³H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC₅₀ of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P₂ fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[³H]glutamate, or to interact with aconitine-induced inhibition of L-[³H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED₅₀9 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED₅₀ = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.