TY - JOUR T1 - Activity of 2-Substituted Lysophosphatidic Acid (LPA) Analogs at LPA Receptors: Discovery of a LPA<sub>1</sub>/LPA<sub>3</sub>Receptor Antagonist JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1173 LP - 1180 DO - 10.1124/mol.60.6.1173 VL - 60 IS - 6 AU - Christopher E. Heise AU - Webster L. Santos AU - Ann M. Schreihofer AU - Brian H. Heasley AU - Yurii V. Mukhin AU - Timothy L. Macdonald AU - Kevin R. Lynch Y1 - 2001/12/01 UR - http://molpharm.aspetjournals.org/content/60/6/1173.abstract N2 - 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. ER -