Medicinal Chemistry

form the inner, hydrophobic part of the lipid bilayer, which behaves as a liquid.
Cholesterol serves to make the bilayer more rigid and less permeable. There are also
glycolipidsin the outer monolayer.

7.2.1 Targeting Specific Membrane Lipids as Putative Receptors

Since the membrane is so vital to cellular functioning, it would seem reasonable that
the lipid component of the cell membrane might be a viable drug target. However, as
discussed in section 2.2, lipids are not ideal molecules to function as putative receptors.
Lipid molecules, unlike peptides, are somewhat structurally bland and do not offer a
complex and unique array of heteroatoms from which to form potential receptors. Also,
insufficient lipid variability from cell to cell may render it difficult to uniquely target
lipids contained within the cells of a particular organ. Accordingly, attempts to target
endogenous lipids within cell membranes as possible drug receptors have been
frequently unsuccessful.
In addition, the notion that “lipid insertion,” or some other lipid-mediated event, is
the mechanism of action for general anesthetics has not withstood the test of time. For
many years it was hypothesized that general anesthetics inserted themselves into mem-
branes, thereby modifying membrane fluidity, which in turn modified membrane func-
tion, in turn producing anesthesia. However, since the mid-1990s this postulate has been
largely rejected and replaced with the observation that most general anesthetics interact
with ligand-gated ion channel proteins such as the GABA-A receptor or the NMDA
receptor. Likewise, the notion that ethanol exerts its CNS-depressant influence exclu-
sively through ethanol–membrane interactions has similarly been downplayed.
Nevertheless, a variety of data do support the possibility of ethanol–membrane interac-
tions. Ethanol is a small lipid-soluble molecule and does dissolve in the lipid bilayer;
nuclear magnetic resonance spectroscopic studies have shown that ethanol is located
near the membrane surface, with the hydroxyl group anchored to the polar headgroup
of the phospholipids. Other studies support the hypothesis that ethanol specifically
interacts with the polar headgroup of phosphatidylcholine, and that ethanol, at physio-
logically attainable levels, dose-dependently decreases the order in brain membranes.
Also, an abnormal lipid, identified as phosphatidylethanol, has been found in the cell
membranes of ethanol-intoxicated rats. Finally, cells chronically exposed to ethanol
demonstrate an increased cholesterol content and thus decreased fluidization. Despite
these observations, the role of ethanol in binding to membrane proteins is probably
more pharmacologically relevant than these lipid interactions.
There are a few unique circumstances under which membrane lipids can successfully
be targeted as drug receptors. Since membrane integrity is essential to cell survival, tar-
geting endogenous cell membrane lipids is difficult but targeting exogenous cell mem-
brane lipids is desirable. If there is an unwanted “foreign” cell type within the body, and
if the membrane of this unwanted cell can be uniquely targeted, then designing drugs
to specifically interact with membrane lipids becomes a viable design strategy.
Antifungal agents, such as Amphotericin B, offer a superb example of this strategy.
Amphotericin B has a selective fungicidal effect by exploiting the differences in lipid
composition between fungal and human cell membranes. The predominant sterol in
human cell membranes is cholesterol, whereas ergosterol is the principal cell membrane

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