Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors: Discovery of a LPA1/LPA3 receptor antagonist

C. E. Heise, W. L. Santos, A. M. Schreihofer, B. H. Heasley, Y. V. Mukhin, T. L. Macdonald, K. R. Lynch

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88 Scopus citations


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[-γ35S]) 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[γ35S] 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.

Original languageEnglish
Pages (from-to)1173-1180
Number of pages8
JournalMolecular Pharmacology
Issue number6
StatePublished - 2001


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