CGRP receptor antagonists: design and screening

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.

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.

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.

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.