Activity of 2-Substituted Lysophosphatidic Acid (LPA) Analogs at LPA Receptors: Discovery of a LPA₁/LPA₃Receptor Antagonist

Abstract

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, LPA 1 , LPA 2 , and LPA 3 , provides a platform for developing receptor type-selective ligands. Starting with an Nacyl 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 5Ј-O-(3-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[␥ 35 S] 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 LPA 1 /LPA 3 competitive antagonist. Several compounds that had smaller side chains were found to be LPA 1 -selective agonists.

The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases

“…Ki16425 blocked in vivo tumor cell proliferation and inhibited the production by tumor cells of proosteoclastic cytokines, whereas normal platelet functions were unaffected. Different antagonists targeting LPA 1 and, to a lesser extent, LPA 3 have been described (17,(24)(25)(26). In vitro, the concentration of Ki16425 (10 M) used in this study was suitable with a complete inhibition of LPA 1 (Ki, 0.35 M) and LPA 3 (Ki, 0.93 M; see ref.…”

Lipid Phosphate Phosphatase-1 Regulates Lysophosphatidate-induced Fibroblast Migration by Controlling Phospholipase D2-dependent Phosphatidate Generation

“…wls-31 cannot be hydrolyzed by LPP1. This compound has agonist activity for LPA 1 receptors (50,51) that are expressed in Rat2 fibroblasts. In our work the effects of LPA and wls-31 on migration were inhibited by pertussis toxin, indicating receptor coupling to G␣ i .…”

Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

“…To unveil the LPA receptor subtypes responsible for migration, we compared the effects of several LPA receptor antagonists in rat and human glioma cells (Figure 4b). Ki16425 has a preference for LPA 1 and LPA 3 over LPA 2 (Ohta et al, 2003); similarly, VPC12249 also prefers LPA 1 and LPA 3 but not LPA 2 (Heise et al, 2001), whereas dioctylglycerol pyrophosphate (DGPP 8:0) shows a preference for only LPA 3 (Fischer et al, 2001). VPC12249 and Ki16425, but DGPP 8:0 significantly suppressed the LPA response.…”