Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

Abstract

N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in host defense and sensing cellular dysfunction. Thus, FPRs represent important therapeutic targets. In the present studies, we screened 32 ligands (agonists and antagonists) of unrelated GPCRs for their ability to induce intracellular Ca 2ϩ mobilization in human neutrophils and HL-60 cells transfected with human FPR1, FPR2, or FPR3. Screening of these compounds demonstrated that antagonists of gastrin-releasing peptide/neuromedin B receptors ( -(4-nitrophenyl) Phe-based PD176252/PD168368 analogs and 41 related nonpeptide/nonpeptoid analogs revealed 22 additional FPR agonists. Most were potent mixed FPR1/FPR2/FPR3 agonists with nanomolar EC 50 values for FPR2, making them among the most potent nonpeptide FPR2 agonists reported to date. In addition, these agonists were also potent chemoattractants for murine and human neutrophils and activated reactive oxygen species production in human neutrophils. Molecular modeling of the selected agonists using field point methods allowed us to modify our previously reported pharmacophore model for the FPR2 ligand binding site. This model suggests the existence of three hydrophobic/aromatic subpockets and several binding poses of FPR2 agonists in the transmembrane region of this receptor. These studies demonstrate that FPR agonists could include ligands of unrelated GPCR and that analysis of such compounds can enhance our understanding of pharmacological effects of these ligands.

Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2

“…These field descriptors (or field points) are extrema of electrostatic, steric and hydrophobic fields. 29 Similar to our previous finding, 18,25 the active enantiomers of the ureidopropanamides reported here [( S )- 9b , ( R )- 9c , ( S )- 9d , and ( S )- 9f )] had better alignments than their corresponding inactive enantiomeric conterparts. As examples, overlay of molecular conformations of the enantiomer pair ( R )- and ( S )- 9c is shown in Figure 3.…”

“…To further investigate the enantiomer preference of our FPR2 ligands, all molecules were overlaid on a previously refined three-subpocket pharmacophore model. 18 The highest-score superimpositions together with values of calculated similarity are shown in Table 2. The similarity values depend equally on geometric and field similarity of a molecule and template.…”

“…18 The template contains field points of different types in the positions of energy extrema for probe atoms. Positive probes give “negative” field points, whereas energy extrema for negative and neutral probe atoms correspond to “positive” and steric field points, respectively.…”

“…14). They include (Figure 1): benzimidazole derivatives exemplified by compound 1 , 16 pyridazin-3(2 H )-ones (compound 2 ), 17 N -phenylurea derivatives (compound 3 ), 18 2-( N -piperazinyl)acetamide derivatives (compound 4 ), 16 quinazolinones derivatives such as the highly specific non-peptide FPR2 agonist 5 (designated in most publications as Quin-C1), 19 pyrazolone derivatives as the mixed FPR1/FPR2 agonist 6 (designated in most of publications as “Compound 43”). 20,21 …”

“…25 These studies originated from the finding that antagonists of gastrin-releasing peptide/neuromedin B receptors (bombesin receptors), namely PD-176252 ( 7 ), PD168368 ( 8 ) (Figure 2), and related chiral derivatives, were potent FPR1/FPR2 agonists. 18 We evaluated 22 structural derivatives of compound 7 for their ability to activate human neutrophils and HL-60 cells transfected with human FPR1 or FPR2. While none of the compounds had affinity for bombesin receptors, 15 of the compounds stimulated Ca 2+ flux in FPR1/FPR2 transfected cells.…”