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 (8)(9). Instead, they bind to the ion-channel in order to block the flow of ions, much in the same way that magnesium blocks transport. 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. These are labeled relative to the N/Q/R site (position 0) as their proper orientation within the protein as a whole is still undetermined. The biding reaction of PCP and Ketamine to the NMDA receptor is thought to be stabilized via binding of the antagonist's amino group to these Asn oxygens, while Phe and Leu multi-carbon side-chains form bonds with the hydrophobic edges of the molecules. 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 (10).

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 (10). Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a much higher binding affinity for the NMDA receptor than (r)-Ketamine, yet PCP has shown to have an even greater binding affinity than either. This can cause problems as PCP will bind so strongly that it eventually causes severe damage to the protein structure through its inhibitory nature (8)(11). 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. This binding reaction, and subsequent destruction of the NMDA receptor is thought to be the cause of many neurological disorders involving psychosis such as Schizophrenia. A natural degradation of NMDA receptors may be involved in Alzheimer's Disease (AD) given the receptor's importance in learning and memory (8)(11)(12).

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 (10). Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a much higher binding affinity for the NMDA receptor than (r)-Ketamine, yet PCP has shown to have an even greater binding affinity than either. This can cause problems as PCP will bind so strongly that it eventually causes severe damage to the protein structure through its inhibitory nature (8)(11). Given that PCP is often smoked in recreational abuse, the applied heat causes a reaction that may break the molecule down into 1-phenyl-1-cyclohexene (PC) and piperidine. Despite this, the remaining PCP is most likely the molecule that ultimate binds to the ion-channel, given it's close structural similarities to Ketamine. This binding reaction, and subsequent destruction of the NMDA receptor is thought to be the cause of many neurological disorders involving psychosis such as Schizophrenia. A natural degradation of NMDA receptors may be involved in Alzheimer's Disease (AD) given the receptor's importance in learning and memory (8)(11)(12).

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Revision as of 05:06, 23 April 2011 view source Student (talk \| contribs) students 33,923 edits No edit summary ← Older edit		Revision as of 14:33, 2 May 2011 view source Student (talk \| contribs) students 33,923 edits No edit summary Newer edit →
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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 (8)(9). Instead, they bind to the ion-channel in order to block the flow of ions, much in the same way that magnesium blocks transport. 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. These are labeled relative to the N/Q/R site (position 0) as their proper orientation within the protein as a whole is still undetermined. The biding reaction of PCP and Ketamine to the NMDA receptor is thought to be stabilized via binding of the antagonist's amino group to these Asn oxygens, while Phe and Leu multi-carbon side-chains form bonds with the hydrophobic edges of the molecules. 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 (10).		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 (8)(9). Instead, they bind to the ion-channel in order to block the flow of ions, much in the same way that magnesium blocks transport. 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. These are labeled relative to the N/Q/R site (position 0) as their proper orientation within the protein as a whole is still undetermined. The biding reaction of PCP and Ketamine to the NMDA receptor is thought to be stabilized via binding of the antagonist's amino group to these Asn oxygens, while Phe and Leu multi-carbon side-chains form bonds with the hydrophobic edges of the molecules. 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 (10).

	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 (10). Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a much higher binding affinity for the NMDA receptor than (r)-Ketamine, yet PCP has shown to have an even greater binding affinity than either. This can cause problems as PCP will bind so strongly that it eventually causes severe damage to the protein structure through its inhibitory nature (8)(11). 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. This binding reaction, and subsequent destruction of the NMDA receptor is thought to be the cause of many neurological disorders involving psychosis such as Schizophrenia. A natural degradation of NMDA receptors may be involved in Alzheimer's Disease (AD) given the receptor's importance in learning and memory (8)(11)(12).		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 (10). Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a much higher binding affinity for the NMDA receptor than (r)-Ketamine, yet PCP has shown to have an even greater binding affinity than either. This can cause problems as PCP will bind so strongly that it eventually causes severe damage to the protein structure through its inhibitory nature (8)(11). Given that PCP is often smoked in recreational abuse, the applied heat causes a reaction that may break the molecule down into 1-phenyl-1-cyclohexene (PC) and piperidine. Despite this, the remaining PCP is most likely the molecule that ultimate binds to the ion-channel, given it's close structural similarities to Ketamine. This binding reaction, and subsequent destruction of the NMDA receptor is thought to be the cause of many neurological disorders involving psychosis such as Schizophrenia. A natural degradation of NMDA receptors may be involved in Alzheimer's Disease (AD) given the receptor's importance in learning and memory (8)(11)(12).