Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 3, Issue 2, Pages 305-320Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.9b00108
Keywords
adrenomedullin; calcitonin gene-related peptide; G protein-coupled receptor; allosteric modulator; receptor activity-modifying protein
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Funding
- Health Research Council of New Zealand
- University of Auckland BioPharma Thematic Research Initiative
- Lottery Health Commission of New Zealand
- Auckland Medical Research Foundation Barbara Basham Doctoral Scholarship
- Biotechnology and Biological Sciences Research Council [BB/M006883/1]
- BBSRC [BB/M006883/1] Funding Source: UKRI
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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 beta-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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