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Departments of
Pharmacology (K.R.L., S.J.C., M.Z.) and
Chemistry
(D.W.H., J.G.C., T.L.M.), University of Virginia,
Charlottesville, Virginia 22908
Although lipid phosphoric acid mediators such as lysophosphatidic acid
(LPA) are now recognized widely as intercellular signaling molecules,
the medicinal chemistry of these mediators is poorly developed. With
the goal of achieving a better understanding of the structure activity
relationships in LPA, we have synthesized and tested a series of LPA
analogs that lack the 2-hydroxyl moiety. Our series consisted of
compounds with 2, 3, or 4 carbon diol or amino alcohol backbones and
oleoyl or palmitoleoyl acyl groups. These molecules cannot be acylated
further to form phosphatidic acids, nor do they have chiral centers.
The rank order potency of these compounds in mobilization of calcium in
MDA MB-231 cells suggested a maximum optimal chain length of 24-25
atoms. However, high potency for the inhibition of adenylyl cyclase in
these cells was achieved only by one compound that also contained a
dissociable proton five bond lengths from the phosphorus atom. That
compound, N-oleoyl-2-hydroxyethyl-1-phosphate, was
nearly equipotent to 1-oleoyl LPA in both assays. The striking mimicry
of LPA by the ethanolamine-based compound and the presence of fatty
acid amides in tissue prompts us to propose that phosphorylated
N-acyl ethanolamides occur naturally.
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