OOR― 277 ―Lysophosphatidic acid (LPA) is a bioactive phospholipid, consisting of a phosphate headgroup and a glycerol backbone with a single saturated or unsaturated fatty acid chain (Figure 2), which is produced under physiological and pathophysiological conditions in both cells and extracellular fluids. LPA functions are mediated through a family of G protein-coupled receptors (GPCRs), known as the LPA receptors. In mammals, six LPA receptors (LPA1-6) have been discovered to date, and they are divided into two LPA receptor families according to phylogeny: the endothelial gene (EDG) family (LPA1-3) and the non-EDG family (LPA4-6). These receptors are widely distributed in diverse human tissues.LPA receptors have been involved in various pathological conditions. Among LPA1-6 receptors, LPA1 has been intensively studied due to the relevance to several diseases. On the other hands, LPA4 and LPA5 play major roles in the lymphocyte transmigration and platelet activation, while LPA6 was identified as a critical mediator for human hair growth and is a causal gene of a rare familial form of human hair loss7). However, there have been few reports about significant subtype selective and potent agonists toward LPA4, LPA5 and LPA6 receptors yet. Hence, this project aims to elucidate comprehensive structure-activity relationships (SARs) of LPA4, LPA5 and LPA6, obtain potent and selective agonists targeting the three receptors and acquire lead compounds for the discovery of drug candidates. We synthesized possible combinations of the each module fragment and evaluated the receptor activation functional assay.We found that the mix-and-match strategy based on the three components of LPA (Figure 2) was applicable to LPA analogues. We generated some potent and subtype selective LPA analogues, particularly toward LPA4, LPA5 and LPA6. The present results are just preliminary, and we must continue the research more intensively. From this effort, we hope we can find more potent and more selective agonist for LPA receptors.We thank Prof. Dr. Junken Aoki and his collaborators, Graduate School of Pharmaceutical Sciences, Lysophosphatidic acidHOExperimental MethodsResults and DiscussionPerspectivesAcknowledgmentsOHPOOOHFigure 2. Structure of Lysophsphatidic acid (LysoPA)(LysoPA)
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