Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin‑2 Receptor: Structure–Activity Relationships and Optimization

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.

B类G蛋白偶联受体（G-protein-coupled receptors, GPCRs）仍是药物开发领域尚未被充分挖掘的靶点。其中降钙素受体（calcitonin receptor, CTR）家族极具挑战性，因为其受体为异聚体，由两种不同组分构成：降钙素受体样受体（calcitonin receptor-like receptor, CLR）或降钙素受体（CTR），与三种被称为受体活性修饰蛋白（receptor activity-modifying proteins, RAMPs）的辅助蛋白之一结合。其中CLR/RAMP1构成降钙素基因相关肽（CGRP）受体，CLR/RAMP2构成肾上腺髓质素1（AM1）受体，CLR/RAMP3构成肾上腺髓质素2（AM2）受体；而CTR/RAMP复合物则可形成三种不同的胰岛淀粉样多肽受体。尽管选择性阻断AM2受体具备重要的治疗价值，但抑制AM1受体会引发临床上无法接受的血压升高。本研究通过系统性开展构效关系研究，开发出了首创的AM2受体拮抗剂。这类化合物展现出具有治疗价值的特性，对AM1受体的选择性高达1000倍。上述研究结果凸显了AM2拮抗剂的治疗潜力。