Structure-activity relationships of lysophosphatidic acid: Conformationally restricted backbone mimetics

Lysophosphatidic acid (LPA) has associated with it an intriguing cell biolo gy that is thought to be mediated through its interaction with G-protein co upled receptor(s). In an effort to extend the structure-activity relationsh ips of LPA, we have produced a series of LPA analogues in which the glycero l core in LPA was replaced with conformationally restricted aryl substructu res. The aryl substructures encompassed aminophenol, resorcinol, dihydroxy benzophenone, and tocopherol systems. The benzophenone moiety was investiga ted both as a conformationally restricting substructure for LPA and as a po ssible photoreactive alkylating agent for the LPA receptor(s). All LPA anal ogues were evaluated for their potency and efficacy in mobilizing calcium i ons from internal stores in MDA MB-231 cells. Ten of the 14 analogues exhib ited activity in this assay at doses up to 5 mu M; none of the compounds ex hibited nonreceptor-mediated lytic activity at this maximal concentration. The receptor response showed surprising tolerance for manipulation in the b ackbone region of LPA, although none of the compounds were equipotent to LP A. This tolerance for a variety of structures has given us new leads into t he realization of novel agonists and antagonists of the LPA receptor(s).