Abstract
Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure–activity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists.
Highlights
G-protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, with a broad range of physiological and pathophysiological roles.[1]
Functional complexity and pharmacological diversity of GPCRs can be further influenced by interactions with receptor activitymodifying proteins (RAMPs)
RAMPs are a family of single transmembrane domain proteins that complex with GPCRs to facilitate cell surface trafficking, receptor pharmacology as well as recycling and degradation.[3,4]
Summary
G-protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, with a broad range of physiological and pathophysiological roles.[1]. Regardless, a number of compounds have been reported in the past decade, including synthetic modulators of glucagon, glucagon-like peptide-1, corticotropin-releasing factor 1, and calcitonin receptor-like receptors.[11−13] The most successful target of class B GPCRs for small molecule modulators has been the CGRP receptor (comprising CLR and RAMP1) for which several antagonists and antibodies have been developed in recent years for the treatment of migraine.[14−18] Some of these have reached the market including the two oral small molecule antagonists, rimegepant[19] (Nurtec ODT) and ubrogepant[20] (Ubrelvy), as well as the three injectable signal blocking monoclonal antibodies, erenumab[21] (Aimovig), eptinezumab[22] (Vyepti), and galcanezumab[23] (Emgality). The binding site has been shown by X-ray crystallography studies to be at the interface between RAMP1 and the CLR.[24]
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