Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.
Journal
ACS pharmacology & translational science
ISSN: 2575-9108
Titre abrégé: ACS Pharmacol Transl Sci
Pays: United States
ID NLM: 101721411
Informations de publication
Date de publication:
10 Apr 2020
10 Apr 2020
Historique:
received:
27
11
2019
entrez:
17
4
2020
pubmed:
17
4
2020
medline:
17
4
2020
Statut:
epublish
Résumé
Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a β-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.
Identifiants
pubmed: 32296770
doi: 10.1021/acsptsci.9b00108
pmc: PMC7155196
doi:
Types de publication
Journal Article
Langues
eng
Pagination
305-320Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M006883/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM104251
Pays : United States
Informations de copyright
Copyright © 2020 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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