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Transducer Mechanism: G Protein–Coupled Receptors01:30

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CGRP receptor antagonists: design and screening.

David R Poyner1, Debbie L Hay, Alex C Conner

  • 1Aston University, Life and Health Sciences, Birmingham, B4 7ET, UK.

Expert Opinion on Drug Discovery
|March 14, 2013
PubMed
Summary
This summary is machine-generated.

New non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists show promise for migraine and other conditions. However, current antagonists have low bioavailability, necessitating further structural research for improved drug design.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • Calcitonin gene-related peptide (CGRP) receptor antagonists, including olcegepant and telcagepant, are emerging as treatments for migraine.
  • The development of high-affinity, non-peptide antagonists broadens potential therapeutic applications to conditions like septic shock and angiogenesis inhibition.

Purpose of the Study:

  • To review the structure and signaling properties of the CGRP receptor.
  • To discuss the clinical implications of targeting the CGRP receptor, current antagonist profiles, and screening requirements for new compounds.

Main Methods:

  • Literature review summarizing current knowledge on CGRP receptor structure and function.
  • Analysis of existing non-peptide CGRP receptor antagonists and their binding characteristics.
  • Discussion of screening methodologies for novel antagonists.

Main Results:

  • Current non-peptide antagonists bind to epitopes on both calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1).
  • Low bioavailability of existing antagonists limits their clinical utility.
  • Achieving CGRP receptor selectivity requires targeting regions influenced by both RAMP1 and CLR.

Conclusions:

  • Further structural information of the CGRP receptor is essential for designing novel antagonists.
  • Current screening methods primarily measure CGRP-mediated cAMP changes.
  • Exploring CGRP's influence on other signaling pathways and developing pathway-selective allosteric antagonists may offer future therapeutic strategies, pending further mechanistic understanding.