{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:14:44Z","timestamp":1791144884724,"version":"4.1.0"},"reference-count":0,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[1997,2,15]],"date-time":"1997-02-15T00:00:00Z","timestamp":855964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[1997,2,15]]},"abstract":"<jats:p>1. N\u2010methyl\u2010D\u2010aspartic acid (NMDA)\u2010activated currents were recorded from dissociated rat retinal ganglion cells using whole\u2010cell recording. The NMDA open\u2010channel blocking drug memantine was evaluated for non\u2010competitive and\/or uncompetitive components of antagonism. A rapid superfusion system was used to apply various drugs for kinetic analysis. 2. Dose\u2010response data revealed that memantine blocked 200 microM NMDA\u2010evoked responses with a 50% inhibition constant (IC50) of approximately 1 microM at \u201060 mV and an empirical Hill coefficient of approximately 1. The antagonism followed a bimolecular reaction process. This 1:1 stoichiometry is supported by the fact that the macroscopic blocking rate of memantine (kon) increased linearly with memantine concentration and the macroscopic unblocking rate (koff) was independent of it. The estimated pseudo\u2010first order rate constant for macroscopic blockade was 4 x 10(5) M\u20101 S\u20101 and the rate constant for unblocking was 0.44 s\u20101. Both the blocking and unblocking actions of memantine were well fitted by a single exponential process. 3. The kon for 2 microM memantine decreased with decreasing concentrations of NMDA. By analysing kon behaviour, we estimate that memantine has minimal interaction with the closed\u2010unliganded state of the channel. As channel open probability (Po) approached zero, a small residual action of memantine may be explained by the presence of endogenous glutamate and glycine. 4. Memantine could be trapped within the NMDA\u2010gated channel if it was suddenly closed by fast washout of agonist. The measured gating process of channel activation and deactivation appeared at least 10\u201020\u2010fold faster than the kinetics of memantine action. By combining the agonist and voltage dependence of antagonism, a trapping scheme was established for further kinetic analysis. 5. With low agonist concentrations, NMDA\u2010gated channels recovered slowly from memantine blockade. By analysing the probability of a channel remaining blocked, we found that memantine binding appeared to stabilize the open conformation of the blocked channel and did not affect ligand affinity. Validity of the \"trapping model' and stabilization of the open conformation were further suggested by agreement between the predicted dose\u2010response curve for NMDA in the presence of 2 microM memantine and the empirically derived dose\u2010response relationship. 6. Based on simple molecular schemes, the degree of blockade at various concentrations of agonist for \"pure' non\u2010competitive vs. uncompetitive inhibition was computer simulated. The measured degree of blockade by 6 microM memantine was close to ideal for pure uncompetitive antagonism. Taken together, we conclude that the predominant mechanism of open\u2010channel blockade by memantine is uncompetitive. In general, the relative magnitude of the dissociation rate of an open\u2010channel blocker from the open but blocked channel (the apparent off\u2010rate) compared with the rate of leaving the closed and blocker\u2010trapped state (the leak rate) will determine the contribution of uncompetitive vs. non\u2010competitive actions, respectively. 7. Millimolar internal Cs+ competed with memantine for binding in the NMDA\u2010gated channel, and reduced the association rate of memantine, but had no effect on the voltage dependence of the dissociation rate. After removal of Cs+, the calculated Ki for memantine remained voltage dependent. These observations would be difficult to reconcile with models in which memantine binds to a site outside the channel pore and instead strongly support the supposition that the blocking site for memantine is within the permeation pathway.<\/jats:p>","DOI":"10.1113\/jphysiol.1997.sp021909","type":"journal-article","created":{"date-parts":[[2014,12,17]],"date-time":"2014-12-17T06:08:12Z","timestamp":1418796492000},"page":"27-46","source":"Crossref","is-referenced-by-count":247,"title":["Mechanism of memantine block of NMDA\u2010activated channels in rat retinal ganglion cells: uncompetitive antagonism."],"prefix":"10.1113","volume":"499","author":[{"given":"H S","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S A","family":"Lipton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[1997,2,15]]},"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.1997.sp021909","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.1997.sp021909","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T16:04:36Z","timestamp":1698422676000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.1997.sp021909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,2,15]]},"references-count":0,"journal-issue":{"issue":"1","published-print":{"date-parts":[[1997,2,15]]}},"alternative-id":["10.1113\/jphysiol.1997.sp021909"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.1997.sp021909","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,2,15]]}}}