N-palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids are selective competitive antagonists of the lysophosphatidic acid receptors.

Lysophosphatidic acid is the best characterized member of a lipid mediator family with growth factor-like activities that act through a class of G protein-coupled plasma membrane receptors. In Xenopus laevis oocytes, lysophosphatidate activates at least two pharmacologically distinct receptor subtypes distinguished by 1-acyl-sn-glycero-2,3-cyclic phosphate. Both of these naturally occurring ligands elicit oscillatory Cl- currents in the oocyte through G protein-coupled activation of the phosphoinositide/Ca2+ second messenger system, which in turn leads to the opening of Ca(2+)-activated Cl- channels. We developed an improved chemical synthesis and purification procedure for two N-acylated amino acid phosphates. N-Palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids inhibited the lysophosphatidate-activated Cl- currents with IC50 values of 5.4 +/- 0.7 and 6.5 +/- 1.5 nM at the high affinity site and 805 +/- 97 and 172 +/- 36 nM at the low affinity receptor site, respectively. In selective activation of the cyclic lysophosphatidate receptor, IC50 values of 330 +/- 30 and 490 +/- 40 nM were obtained, respectively. The D- and L-stereoisomers were equally effective when applied extracellularly. In contrast, they were ineffective when microinjected into the oocyte, indicating an extracellular site of inhibition. The inhibitors did not alter currents elicited by the different acetylcholine, serotonin, and glutamate receptors expressed heterologously in the oocyte. Pharmacological analysis of the results indicates that N-palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids are potent and specific competitive inhibitors of the lysophosphatidate receptors in the X. laevis oocyte.