Dataset Information

Formyl peptide receptor type 2 agonists to kick-start resolution pharmacology.

ABSTRACT: One way to develop innovative approaches for the treatment of chronic diseases is to exploit the biology of the resolution of inflammation. With this terminology, we identify the integrated and complex network of mediators and pathways that ensure a timely and spatially regulated inflammatory response. Pro-resolving mediators act on specific receptors. This provides an opportunity for developing a new arm of pharmacology we have termed "resolution pharmacology." Here we present the reasoning behind the need to develop new medicines based on resolution and use a prototype GPCR as an example. Understanding how the formyl peptide receptor type 2 (FPR2) operates in a cell-specific manner can guide the development of agonists as new therapeutics that could be of benefit as a therapy or co-therapy for several diseases that affect our society. FPR2 agonists would be among the first drugs to establish "resolution pharmacology" as the pharmacological approach for the third decade of the millennium.

SUBMITTER: Perretti M

PROVIDER: S-EPMC7520433 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Formyl peptide receptor type 2 agonists to kick-start resolution pharmacology.

Perretti Mauro M Godson Catherine C

British journal of pharmacology 20200920 20

One way to develop innovative approaches for the treatment of chronic diseases is to exploit the biology of the resolution of inflammation. With this terminology, we identify the integrated and complex network of mediators and pathways that ensure a timely and spatially regulated inflammatory response. Pro-resolving mediators act on specific receptors. This provides an opportunity for developing a new arm of pharmacology we have termed "resolution pharmacology." Here we present the reasoning beh ...[more]

PMID: 32954491

Similar Datasets

Project description: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 Ca²+ 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 (BB₁/BB₂) PD168368 [(S)-a-methyl-a-[[[(4-nitrophenyl)amino]carbonyl]amino]-N-[[1-(2-pyridinyl) cyclohexyl]methyl]-1H-indole-3-propanamide] and PD176252 [(S)-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]-a-methyl-a-[[-(4-nitrophenyl)amino]carbonyl]amino-1H-indole-3-propanamide] were potent mixed FPR1/FPR2 agonists, with nanomolar EC₅₀ values. Cholecystokinin-1 receptor agonist A-71623 [Boc-Trp-Lys(ε-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH₂] was also a mixed FPR1/FPR2 agonist, but with a micromolar EC₅₀. Screening of 56 Trp- and 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 EC₅₀ 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.

Dataset Information

Formyl peptide receptor type 2 agonists to kick-start resolution pharmacology.

Publications

Formyl peptide receptor type 2 agonists to kick-start resolution pharmacology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets