Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H1 Receptor.
| Title: | Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H1 Receptor. |
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| Authors: | Kok ZY; Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, U.K.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, the Midlands, Nottingham NG7 2UH, U.K.; Stoddart LA; Division of Physiology, Pharmacology & Neuroscience, Medical School, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, the Midlands, Nottingham NG7 2UH, U.K.; Mistry SJ; Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, U.K.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, the Midlands, Nottingham NG7 2UH, U.K.; Mocking TAM; Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelean 1083, 1083 HV Amsterdam, The Netherlands.; Vischer HF; Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelean 1083, 1083 HV Amsterdam, The Netherlands.; Leurs R; Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelean 1083, 1083 HV Amsterdam, The Netherlands.; Hill SJ; Division of Physiology, Pharmacology & Neuroscience, Medical School, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, the Midlands, Nottingham NG7 2UH, U.K.; Mistry SN; Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, U.K.; Kellam B; Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, U.K.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, the Midlands, Nottingham NG7 2UH, U.K. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2022 Jun 23; Vol. 65 (12), pp. 8258-8288. Date of Electronic Publication: 2022 Jun 03. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Receptors, Histamine H1*/metabolism ; Histamine*; Fluorescent Dyes/metabolism ; Receptors, Histamine/metabolism ; Humans ; Ligands ; Molecular Docking Simulation ; Peptides |
| Abstract: | The histamine H1 receptor (H1R) has recently been implicated in mediating cell proliferation and cancer progression; therefore, high-affinity H1R-selective fluorescent ligands are desirable tools for further investigation of this behavior in vitro and in vivo. We previously reported a H1R fluorescent ligand, bearing a peptide-linker, based on antagonist VUF13816 and sought to further explore structure-activity relationships (SARs) around the linker, orthostere, and fluorescent moieties. Here, we report a series of high-affinity H1R fluorescent ligands varying in peptide linker composition, orthosteric targeting moiety, and fluorophore. Incorporation of a boron-dipyrromethene (BODIPY) 630/650-based fluorophore conferred high binding affinity to our H1R fluorescent ligands, remarkably overriding the linker SAR observed in corresponding unlabeled congeners. Compound 31a, both potent and subtype-selective, enabled H1R visualization using confocal microscopy at a concentration of 10 nM. Molecular docking of 31a with the human H1R predicts that the optimized peptide linker makes interactions with key residues in the receptor. |
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| Grant Information: | G0800006 United Kingdom MRC_ Medical Research Council; MR/N020081/1 United Kingdom MRC_ Medical Research Council; MR/NO20081/1 United Kingdom MRC_ Medical Research Council |
| Substance Nomenclature: | 0 (Fluorescent Dyes); 0 (Ligands); 0 (Peptides); 0 (Receptors, Histamine); 0 (Receptors, Histamine H1); 820484N8I3 (Histamine) |
| Entry Date(s): | Date Created: 20220623 Date Completed: 20220624 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9234962 |
| DOI: | 10.1021/acs.jmedchem.2c00125 |
| PMID: | 35734860 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't