Mechanism Of Action

Most investigators agree that the behavioral effects of PCP are mediated predominantly through RECEPTORS, which are proteins that are important for the normal functioning of cells within the body. Phencyclidine acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor-channel complex, which is one type of excitatory amino-acid receptor that is selectively activated by the agonists NMDA and GLUTAMATE. By definition, agonists produce stimulation while antagonists block the effects of agonists. When either glutamate or NMDA bind to the receptor, a channel within the cell membrane opens to allow sodium, calcium, and potassium ions to flow into and out of the cell. This movement of ions across the cell membrane causes a depolarization of the membrane which, if sufficiently large, causes the cell to fire. When the cell fires, an electrical charge passes along its membrane and NEUROTRANSMITTERS (chemicals that allow cells to communicate with each other) are released. Thus, glutamate and NMDA are important for normal cell-to-cell communication within the body.

PCP, as well as TCP, ketamine, dizocilpine (MK-801), and SKF 10,047 is representative of compounds that act as noncompetitive antagonists at the NMDA-receptor complex. The binding site for PCP resides within the channel and binding to this site physically prevents calcium and sodium ions from entering the cell while at the same time preventing potassium ions from leaving the cell. Blocking the movement of ions through the cell membrane in turn prevents the neuron from firing. In contrast to the noncompetitive antagonists, competitive antagonists such as CGS 19755, NPC 12626, CPP, and AP5 bind to the NMDA receptor itself without causing the ion channel to open. By simply occupying the receptor without activating it, competitive antagonists prevent NMDA from binding to and activating the receptor. Unlike noncom-petitive antagonists, competitive NMDA-antago-nist effects can be surmounted by higher doses of the agonist. However, the end result of both non-competitive and competitive antagonists is a reduction of neuronal firing.

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