Sandbox42: Difference between revisions
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Molecules such as Phencyclidine (PCP), Ketamine, and dizocilpine (MK-801) are known to block the flow of ions through the NMDA receptor. These molecules are non-competitive antagonists because they do not interfere with either the Glutamate or Glycine/D-Serine active sites. Instead, they bind to the ion-channel, similarly to magnesium. Given that the crystal structure of the ion-channel binding site has not yet been proven, it is difficult to pin down the roles of each residue in channel-blockage binding. However, there is evidence that the ideal binding site for these molecules occurs along side-chain oxygens of Asn 0 Residues, Phe and Leu at -1, Met +25, Val +28, and Ala +29. The pore itself is about 5.5 Angstroms in diameter which suggests the vast majority of blockers bind at the entrance to this very narrow section. | Molecules such as Phencyclidine (PCP), Ketamine, and dizocilpine (MK-801) are known to block the flow of ions through the NMDA receptor. These molecules are non-competitive antagonists because they do not interfere with either the Glutamate or Glycine/D-Serine active sites. Instead, they bind to the ion-channel, similarly to magnesium. Given that the crystal structure of the ion-channel binding site has not yet been proven, it is difficult to pin down the roles of each residue in channel-blockage binding. However, there is evidence that the ideal binding site for these molecules occurs along side-chain oxygens of Asn 0 Residues, Phe and Leu at -1, Met +25, Val +28, and Ala +29. The pore itself is about 5.5 Angstroms in diameter which suggests the vast majority of blockers bind at the entrance to this very narrow section. | ||
As shown in figures 1 | As shown in figures 1-3, Ketamine, PCP, and MK-801 all share similar cyclic carbon structures which can easily bind and block such a narrow opening. Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a four-fold increase in binding affinity for the NMDA receptor. PCP has shown to have an even greater binding affinity, to the point where it causes severe damage to the protein structure through its inhibitory nature. Given that PCP is often smoked in recreational abuse, the heat causes a reaction that breaks the molecule down into 1-phenyl-1-cyclohexene (PC) and piperidine. PC is most likely the molecule that ultimate binds to the ion-channel, given it's close structural similarities to Ketamine. | ||
[[Image:(S)Ketamine3.png|Figure 1: S-Ketamine Structure]] | [[Image:(S)Ketamine3.png|Figure 1: S-Ketamine Structure]] | ||
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Figure 2: PCP in reaction with heat. | Figure 2: PCP in reaction with heat. | ||
[[Image:MK801.png|Figure 3: MK-801]] | |||
Figure 2: Structure of MK-801 | |||
