In vitro neuroprotection by substituted guanidines with varying affinities for the N-methyl-D-aspartate receptor ionophore and for sigma sites

Radioligand binding techniques were used to determine the affinity of a series of substituted guanidine derivatives for 1) the binding site within the ion channel of the N-methyl-D-aspartate (NMDA) receptor, as defined by displacement of MK-801 ([3H]dizocilpine) and 2) sigma sites as defined by disp...

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Bibliographic Details
Published in:	The Journal of pharmacology and experimental therapeutics Vol. 271; no. 2; p. 1080
Main Authors:	Kirk, C J, Reddy, N L, Fischer, J B, Wolcott, T C, Knapp, A G, McBurney, R N
Format:	Journal Article
Language:	English
Published:	United States 01-11-1994
Subjects:	Animals Cells, Cultured Dizocilpine Maleate - metabolism Glutamic Acid - toxicity Guanidines - metabolism Guanidines - pharmacology Ion Channels - metabolism Neurons - drug effects Rats Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - metabolism Receptors, sigma - metabolism Structure-Activity Relationship
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Summary:	Radioligand binding techniques were used to determine the affinity of a series of substituted guanidine derivatives for 1) the binding site within the ion channel of the N-methyl-D-aspartate (NMDA) receptor, as defined by displacement of MK-801 ([3H]dizocilpine) and 2) sigma sites as defined by displacement of [3H]N,N'-di-(o-tolyl)guanidine. The goal was to find ligands with high affinity and selectivity for the NMDA receptor ion-channel site. The neuroprotective activity of these compounds was assessed by their ability to protect cortical neurons from injury caused by a 5-min exposure to 500 microM glutamate in vitro. Release of lactate dehydrogenase into the culture medium by damaged neurons was used as an index of neuronal injury. The 14 compounds tested had IC50 values ranging from 37.3 nM to 12.7 microM for the NMDA receptor ion-channel site and from 8.3 nM to 7.25 microM for sigma sites. Affinity for the ion-channel site was improved by unsymmetrical substitutions on the guanidine moiety. All compounds in the series protected cortical neurons against glutamate toxicity, with EC50 values (concentration affording 50% protection) ranging from 0.38 to 28.25 microM. The neuroprotective effect of each compound was positively correlated with its ion-channel site affinity (r = 0.94); no correlation between neuroprotective efficacy and sigma site binding affinity was found (r V -0.13) establishing clearly that neuroprotection in this assay was linked to NMDA antagonist properties.
ISSN:	0022-3565