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Papers of the Week

Papers: 18 Apr 2020 - 24 Apr 2020

Pharmacology/Drug Development


2020 Apr 10

ACS Pharmacol Transl Sci



Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.


Hendrikse ER, Liew LP, Bower RL, Bonnet M, Jamaluddin MA, Prodan N, Richards KD, Walker CS, Pairaudeau G, Smith DM, Rujan R-M, Sudra R, Reynolds CA, Booe JM, Pioszak AA, Flanagan JU, Hay MP, Hay DL
ACS Pharmacol Transl Sci. 2020 Apr 10; 3(2):305-320.
PMID: 32296770.


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.