ArticleACS pharmacology & translational science2020
Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.
Article in ACS pharmacology & translational science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed, 19 citations in OpenAlex.
- Clinical Potential of Adrenomedullin Signaling in the Cardiovascular System.Circulation research · 2023Review
- Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins.Pharmacological reviews · 2023Review
- Pharmacological characterisation of mouse calcitonin and calcitonin receptor-like receptors reveals differences compared with human receptors.British journal of pharmacology · 2022Article
- Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.Frontiers in physiology · 2022Article
- Energy and reactivity profile and proton affinity analysis of rimegepant with special reference to its potential activity against SARS-CoV-2 virus proteins using molecular dynamics.Journal of molecular modeling · 2021Article
- CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells.Communications biology · 2021Article
- Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure-Activity Relationships and Optimization.Journal of medicinal chemistry · 2021Article
- Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor.ACS pharmacology & translational science · 2020Article
- Editorial for Advances in G Protein-Coupled Receptor Signal Transduction Special Issue.ACS pharmacology & translational science · 2020Article
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.