IMPORTANCE OF THE FIELD: Calcitonin gene-related peptide (CGRP) receptor 
antagonists have recently come to attention with the development of olcegepant 
and telcagepant for the treatment of migraine. The availability of 
high-affinity, non-peptide antagonists opens the way for trials of these 
compounds in other conditions where CGRP antagonism might be useful, such as 
septic shock and inhibition of angiogenesis.
AREAS COVERED IN THIS REVIEW: This review summarises knowledge about the 
structure and signalling properties of the CGRP receptor. The clinical 
ramifications of targeting the CGRP receptor, the profiles of existing 
antagonists and the requirements for screening new compounds will be discussed.
WHAT THE READER WILL GAIN: Readers will gain an overview of how current 
non-peptide antagonists seem to bind similar epitopes contributed by both 
calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 
1 (RAMP1), the main CGRP receptor subunits. We will discuss how current 
antagonists have low bioavailability, limiting their use. For selectivity at 
CGRP receptors, it will be necessary to target parts of the receptor influenced 
by both RAMP1 and CLR.
TAKE HOME MESSAGE: For the design of radically new antagonists, more structural 
information on the receptor is needed. Current screens are largely based on 
measuring CGRP-mediated changes in cAMP. CGRP receptors can influence other 
signalling pathways and pathway-selective allosteric antagonists may be useful, 
but more information is needed about the mechanism of action of CGRP to assess 
the value of this.