Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation

Area of Science:

• Pharmacology
• Biochemistry
• Neuroscience

Background:

• Migraine affects 15% of adults, with current treatments like triptans and CGRP inhibitors having limitations.
• Calcitonin gene-related peptide (CGRP) and its receptor (CLR/RAMP1) are key targets for migraine therapy.
• Existing anti-CGRP antibodies may not fully reduce CGRP levels or reach target cells, necessitating alternative strategies.

Purpose of the Study:

• To explore novel anti-CGRP therapeutics for migraine.
• To investigate chimeric adrenomedullin/adrenomedullin 2 peptides as CLR/RAMP1 receptor antagonists.
• To evaluate the therapeutic potential of self-assembling liquid gels formed by these antagonists.

Main Methods:

• Screening of chimeric adrenomedullin/adrenomedullin 2 peptides for CLR/RAMP1 receptor antagonism.
• Characterization of self-assembly into liquid gels (e.g., ADE651 at 6-20%).
• Assessment of gel-formation impact on molecular passage and in vivo pharmacokinetics and pharmacodynamics in rats.

Main Results:

• Several chimeric peptides, including ADE651, were identified as potent CLR/RAMP1 receptor antagonists.
• ADE651 forms stable liquid gels, slowing molecular passage and enabling sustained circulation (>1 week) after subcutaneous injection in rats.
• ADE651 gel significantly inhibited CGRP-induced vasodilation in rat hindlimbs.

Conclusions:

• Gel-forming CLR/RAMP1 receptor antagonists, like ADE651, offer sustained CGRP inhibition.
• These novel antagonists may provide a promising therapeutic approach for migraine patients unresponsive to existing treatments.
• Targeting CGRP and/or adrenomedullin pathways with sustained-release formulations holds potential for headache management.