Vol. 63, Issue 5, 1032-1042, May 2003

Fatty Alcohol Phosphates are Subtype-Selective Agonists and Antagonists of Lysophosphatidic Acid Receptors

Tamas Virag, Don B. Elrod,¹ Karoly Liliom, Vineet M. Sardar, Abby L. Parrill, Kazuaki Yokoyama, Gangadhar Durgam, Wenlin Deng, Duane D. Miller, and Gabor Tigyi

Departments of Physiology (T.V., K.Y., W.D., G.T.) and Pharmaceutical Sciences (D.B.E., G.D., D.D.M.), University of Tennessee Health Science Center, Memphis, Tennessee; Department of Chemistry and Computational Research on Materials Institute, University of Memphis, Memphis, Tennessee (V.M.S., A.L.P.); and Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary (K.L.)

A more complete understanding of the physiological and pathological role of lysophosphatidic acid (LPA) requires receptor subtype-specific agonists and antagonists. Here, we report the synthesis and pharmacological characterization of fatty alcohol phosphates (FAP) containing saturated hydrocarbon chains from 4 to 22 carbons in length. Selection of FAP as the lead structure was based on computational modeling as a minimal structure that satisfies the two-point pharmacophore developed earlier for the interaction of LPA with its receptors. Decyl and dodecyl FAPs (FAP-10 and FAP-12) were specific agonists of LPA₂ (EC₅₀ = 3.7 ± 0.2 µM and 700 ± 22 nM, respectively), yet selective antagonists of LPA₃ (K_i = 90 nM for FAP-12) and FAP-12 was a weak antagonist of LPA₁. Neither LPA₁ nor LPA₃ receptors were activated by FAPs; in contrast, LPA₂ was activated by FAPs with carbon chains between 10 and 14. Computational modeling was used to evaluate the interaction between individual FAPs (8 to 18) with LPA₂ by docking each compound in the LPA binding site. FAP-12 displayed the lowest docked energy, consistent with its lower observed EC₅₀. The inhibitory effect of FAP showed a strong hydrocarbon chain length dependence with C12 being optimum in the Xenopus laevis oocytes and in LPA₃-expressing RH7777 cells. FAP-12 did not activate or interfere with several other G-protein-coupled receptors, including S1P-induced responses through S1P_1,2,3,5 receptors. These data suggest that FAPs are ligands of LPA receptors and that FAP-10 and FAP-12 are the first receptor subtype-specific agonists for LPA₂.