Role of lipid solubility in the interaction of drugs with the N-methyl-D-aspartate receptor

• Published in: Synapse (New York, N.Y.) Vol. 5; no. 1; p. 71
• Main Authors: Reynolds, I J, Rush, E A
• Format: Journal Article
• Language: English
• Published: United States 1990
• Subjects: Alcohols - pharmacology; Animals; Antidepressive Agents, Tricyclic - pharmacology; Dibenzocycloheptenes - metabolism; Dizocilpine Maleate; Membrane Lipids - metabolism; Phenothiazines - pharmacology; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter - drug effects; Solubility
• ISSN: 0887-4476
• DOI: 10.1002/syn.890050107

We have examined the hypothesis that phenothiazines and tricyclic antidepressants interact with the N-methyl-D-aspartate (NMDA) receptor by mimicking the actions of Zn2+. Using [3H]MK801 binding to well-washed rat brain membranes, we found a disparity between the concentrations of drug required to inhibit [3H]MK801 binding and those necessary to alter dissociation of [3H]MK801 from its binding site. These data suggest that the Zn2+ site is probably not the principle site by which tricyclic drugs inhibit NMDA receptor responses. To determine whether the effects of tricyclic drugs on the dissociation of [3H]MK801 could be explained simply by membrane stabilization, we examined the effect of a series of alcohols. Ethanol, isopropanol, butanol, hexanol, and heptanol all inhibited [3H]MK801 binding. However, with the exception of heptanol, none of the molecules altered the dissociation rate. Thus, while lipid solubility may be an important factor underlying the interactions of some drugs with the NMDA receptor, it is not sufficient to explain the effects of tricyclic antidepressants and phenothiazines in this system.