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Vol. 60, Issue 6, 1173-1180, December 2001
Departments of Pharmacology (C.E.H., A.M.S., K.R.L.) and Chemistry
(W.L.S., B.H.H., T.L.M.), University of Virginia, Charlottesville,
Virginia; and Department of Medicine (Nephrology Division) (Y.V.M.),
Medical University of South Carolina, Charleston, South
Carolina
The physiological implications of lysophosphatidic acid occupancy of
individual receptors are largely unknown because selective agonists/antagonists are unavailable currently. The molecular cloning
of three high-affinity lysophosphatidic acid receptors, LPA1, LPA2, and LPA3, provides a
platform for developing receptor type-selective ligands. Starting with
an N-acyl ethanolamide phosphate LPA analog, we made a
series of substitutions at the second carbon to generate compounds with
varying spatial, stereochemical, and electronic characteristics.
Analysis of this series at each recombinant LPA receptor using a
guanosine 5'-O-(3-[35S]thio)triphosphate
(GTP[
35S]) binding assay revealed sharp differences in
activity. Our results suggest that these receptors have one spatially
restrictive binding pocket that interacts with the 2-substituted
moieties and prefers small hydrophobic groups and hydrogen
bonding functionalities. The agonist activity predicted by the
GTP[35S] binding assay was reflected in the activity
of a subset of compounds in increasing arterial pressure in
anesthetized rats. One compound with a bulky hydrophobic group
(VPC12249) was a dual LPA1/LPA3 competitive
antagonist. Several compounds that had smaller side chains were found
to be LPA1-selective agonists.
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