학술논문
Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H 1 Receptor.
Document Type
Academic Journal
Author
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
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
Subject
Language
English
Abstract
The histamine H 1 receptor (H 1 R) has recently been implicated in mediating cell proliferation and cancer progression; therefore, high-affinity H 1 R-selective fluorescent ligands are desirable tools for further investigation of this behavior in vitro and in vivo. We previously reported a H 1 R 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 H 1 R 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 H 1 R fluorescent ligands, remarkably overriding the linker SAR observed in corresponding unlabeled congeners. Compound 31a , both potent and subtype-selective, enabled H 1 R visualization using confocal microscopy at a concentration of 10 nM. Molecular docking of 31a with the human H 1 R predicts that the optimized peptide linker makes interactions with key residues in the receptor.