Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine

Abstract

The clinical effectiveness of antagonizing the calcitonin gene-related peptide (CGRP) receptor for relief of migraine pain has been clearly demonstrated, but the road to the development of these small molecule antagonists has been daunting. The key hurdle that needed to be overcome was the CGRP receptor itself. The vast majority of the current antagonists recognize similar epitopes on the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). RAMP1 is a relatively small, single, transmembrane-spanning protein and along with the G-protein-coupled receptor CLR comprise a functional CGRP receptor. The tri-helical extracellular domain of RAMP1 plays a key role in the high affinity binding of CGRP receptor antagonists and drives their species-selective pharmacology. Over the years, a significant amount of mutagenesis data has been generated to identify specific amino acids or regions within CLR and RAMP1 that are critical to antagonist binding and has directed attention to the CLR/RAMP1 extracellular domain (ECD) complex. Recently, the crystal structure of the CGRP receptor ECD has been elucidated and not only reinforces the early mutagenesis data, but provides critical insight into the molecular mechanism of CGRP receptor antagonism. This review will highlight the drug design hurdles that must be overcome to meet the desired potency, selectivity and pharmacokinetic profile while retaining drug-like properties. Although the development of these antagonists has proved challenging, blocking the CGRP receptor may one day represent a new way to manage migraine and offer hope to migraine sufferers.

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…CGRP receptors could be shown by PET imaging particularly in cerebellum and brainstem [143] [153]. The structural units CLR and RAMP1 have been found in middle meningeal, middle cerebral pial and superficial temporal arteries [140] [154].…”

“…Combinations of RAMP 2 and 3 subtypes with CLR which can bind also CGRP but with lower affinity and preferring adrenomedullin (AM) (AM > αCGRP > amylin > calcitonin; [147]) form the adrenomedullin receptors 1 and 2 (AM1 and AM2). Combinations of RAMP 1 -3 with the calcitonin receptor (CTR) result in the amylin receptors (AMY) 1 -3 [143] [148]. AM, CT and AMY receptors are of importance for the characterization of selectivity CGRP ligands.…”

“…CGRPs: αCGRP (outside the central nervous system in TRPV1-expressing and capsaicin sensitive primary sensory neurons) and ßCGRP (not encoded by calcitonin gene and found in intrinsic neurons of the gut) [143] [149].…”

“…The intracranial CGRP . The CGRP receptor is a G protein-coupled receptor which is comprised of a multimeric complex including the calcitonin receptor like receptor (orphan receptor CLR; member of secretin family/class B) [143], as well as an accessory protein (receptor activity modifying membrane protein 1; RAMP 1) which includes a 148 a.a.r peptide with a single transmembrane domain [144] [145] and an intracellular protein (receptor component protein; RCP) [140] [146]. Combinations of RAMP 2 and 3 subtypes with CLR which can bind also CGRP but with lower affinity and preferring adrenomedullin (AM) (AM > αCGRP > amylin > calcitonin; [147]) form the adrenomedullin receptors 1 and 2 (AM1 and AM2).…”

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“…Despite these gray areas, they have found numerous applications in drug development and lead target identification 28 . Many GPCR antagonists have been developed using this concept 29 .…”