The molecular pharmacology of lysophosphatidate signaling.

Lysophosphatidic acid (LPA) is the first intermediate in the de novo phospholipid biosynthetic pathway and is now widely recognized as an authentic phospholipid mediator. LPA evokes a variety of biological responses in numerous cell types, including platelet aggregation,1,2 smooth muscle contraction,3,4 cell morphology changes, and mitogenic effects.5 LPA acts as an endogenous ligand for receptors coupled to heterotrimeric proteins Gq, Gi, and G13. Therefore, calcium mobilization, 6 decreases in cAMP levels,7 and (more recently) GTPγS binding assays8 have been convenient methods of measuring LPA-mediated responses. Cloning of several cDNAs that code for putative LPA receptors revealed the EDG (endothelial differentiation gene) family of receptors, which displays some homology with the cannabinoid and melanocortin receptors.9–13 The EDG-2, -4, and -7 genes appear to encode LPA receptors. However, our understanding of the interaction between LPA and its receptors remains limited.14,15 Elucidation of the LPA-receptor mechanism is a formidable task. Development of structure-activity relationships (SARs) is essential and also should help to identify novel lipid mediators that are structurally similar to LPA, but may have different biological activities. As one would expect for ligand-receptor interaction, stereochemical discrimination by the putative receptor must be observed. Although we now have a better understanding of LPA-receptor interaction, more evidence is needed to fully characterize LPA as an authentic intercellular signaling molecule and to identify receptor-selective analogues. An LPA pharmacophore (FIG. 1) has been postulated to consist of three substructural domains: a phosphate head group, a linker region, and a lipophilic tail.16 As part of our continued interest in the SAR of LPA and related lipid phosphoric acid mediators, we have concentrated our investigations on the effects of structural alterations of these domains by evaluating the biological responses of the receptor(s). In order to better elucidate key SAR features, we have begun to develop a library of metabolically stable and more water-soluble LPA mimetics and blockers. Obviously, the development of potent and selective LPA agonists and antagonists would allow for discrimination of LPA subtype–mediated intercellular signals and physiological responses. Moreover, we intend to further investigate the stereochemical demand of