RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1173
OP 1180
DO 10.1124/mol.60.6.1173
VO 60
IS 6
A1 Heise, Christopher E.
A1 Santos, Webster L.
A1 Schreihofer, Ann M.
A1 Heasley, Brian H.
A1 Mukhin, Yurii V.
A1 Macdonald, Timothy L.
A1 Lynch, Kevin R.
YR 2001
UL http://molpharm.aspetjournals.org/content/60/6/1173.abstract
AB 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.