| Abstract
| - Lysophosphatidic acid (LPA) has associated with it an intriguing cell biology that is thoughtto be mediated through its interaction with G-protein coupled receptor(s). In an effort to extendthe structure−activity relationships of LPA, we have produced a series of LPA analogues inwhich the glycerol core in LPA was replaced with conformationally restricted aryl substructures.The aryl substructures encompassed aminophenol, resorcinol, dihydroxy benzophenone, andtocopherol systems. The benzophenone moiety was investigated both as a conformationallyrestricting substructure for LPA and as a possible photoreactive alkylating agent for the LPAreceptor(s). All LPA analogues were evaluated for their potency and efficacy in mobilizingcalcium ions from internal stores in MDA MB-231 cells. Ten of the 14 analogues exhibitedactivity in this assay at doses up to 5 μM; none of the compounds exhibited nonreceptor-mediatedlytic activity at this maximal concentration. The receptor response showed surprising tolerancefor manipulation in the backbone region of LPA, although none of the compounds wereequipotent to LPA. This tolerance for a variety of structures has given us new leads into therealization of novel agonists and antagonists of the LPA receptor(s).
|
