Pharmacological characterization of formyl peptide receptors.

摘要

The formyl peptide receptors including FPR and FPRL1 are G-protein coupled chemoattractant receptors. They are involved in the mobilization of phagocytic leukocytes and subsequent activation of biological functions such as degranulation and superoxide generation. To facilitate the pharmacological characterization of formyl peptide receptors, a compound library with more than fifteen thousand molecules were screened and Quin-C1, a novel small chemical agonist for FPRL1, was discovered. Quin-C1 selectively stimulated FPRL1 and mediated various leukocyte functions including chemotaxis and degranulation. Additional ligands, Quin-C, Quin-M and Quin-O series, were generated through chemical modification of the hit compound. Based on structure-activity relationship analysis, the modified C-series ligands transitioned from a fully efficacious agonist (Quin-C1), to partial agonists/antagonists (Quin-C5 and Quin-C8) and a pure antagonist (Quin-C7). In addition, the Quin-O series molecules, which are structurally quite different from Quin-C derivatives but share quinazolinone backbone, produced a potential FPRL1 antagonist, Quin-O9. Furthermore, Quin-C7 and C8 displayed antagonistic activity toward FPR. Therefore, it is feasible speculate that there are some key similarities between FPR and FPRL1 ligand binding pockets that confer their ligand selectivity.;To further elucidate the receptor-antagonist interaction and selectivity, we characterized fungal products, cyclosporins, as formyl peptide receptor antagonists. Cyclosporin A (CsA), a potent immunosuppressant, inhibited various fMLF-mediated functions including degranulation, chemotaxis and calcium mobilization. Further analysis demonstrated that CsA was selective antagonist of FPR and its inhibition of fMLF-stimulated leukocyte activation was at the level of receptor-ligand interaction.;In the last section, by using the mutant FPRs found in neutrophils from localized juvenile periodontitis (LJP) patients, I explored the possibility of selective loss of functions secondary to receptor conformational changes. Further understanding of receptor-mediated functional selectivity may be potentially useful in designing novel ligands for chemoattractant receptors. A stimulation or inhibition of only selected functions could potentially limit the unwanted effects such as tissue damages due to release of ROS from neutrophils in chronic inflammatory disorders.