Pharmacological regulation of the phencyclidine-binding site associated with the N-methyl-D-aspartate receptor-operated ion channel

K. M. Johnson, L. D. Snell, A. I. Sacaan, S. M. Jones

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The ion channel operated by N-methyl-D-aspartate (NMDA) receptor agonists is modified by several positive and negative effectors. A variety of chemical structures are known to antagonize the effects of NMDA agonists by preferentially binding with high affinity to the open state of the ion channel. Binding of two of these noncompetitive antagonists has been studied extensively in recent months as a probe of NMDA receptor function. It has been found that NMDA agonists and antagonists increase and decrease, respectively, the binding of 3H-TCP or 3H-MK-801 by altering the affinity of the putative phencyclidine (PCP) receptor localized within the ion channel. This affinity change is presumed to be correlated with the conformational change associated with channel opening. This model is also discussed in relationship to one in which binding is increased under nonequilibrium conditions because of a simple increased accessibility to the channel binding site. The modulatory effects of glycine, other amino acids, certain polyamines, and divalent cations on 3H-TCP and/or 3H-MK-801 binding are discussed in relation to their effects on NMDA function in more intact, physiological preparations. It is concluded that the complexity of NMDA receptor regulation provides many possibilities for pharmacological intervention, and that the use of noncompetitive antagonists to probe NMDA receptor function could play a key role in drug development.

Original languageEnglish (US)
Pages (from-to)281-297
Number of pages17
JournalDrug Development Research
Volume17
Issue number4
StatePublished - 1989

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Phencyclidine
N-Methyl-D-Aspartate Receptors
Ion Channels
Phencyclidine Receptors
N-Methylaspartate
Binding Sites
Pharmacology
Dizocilpine Maleate
Divalent Cations
Polyamines
Glycine
Amino Acids
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

Pharmacological regulation of the phencyclidine-binding site associated with the N-methyl-D-aspartate receptor-operated ion channel. / Johnson, K. M.; Snell, L. D.; Sacaan, A. I.; Jones, S. M.

In: Drug Development Research, Vol. 17, No. 4, 1989, p. 281-297.

Research output: Contribution to journalArticle

Johnson, K. M. ; Snell, L. D. ; Sacaan, A. I. ; Jones, S. M. / Pharmacological regulation of the phencyclidine-binding site associated with the N-methyl-D-aspartate receptor-operated ion channel. In: Drug Development Research. 1989 ; Vol. 17, No. 4. pp. 281-297.
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