Structure-guided rational design of dual-target CGRP antagonist/5HT1F agonist therapeutics for migraine.

The strategic design of dual-target ligands concurrently antagonizing calcitonin gene-related peptide (CGRP) receptors and activating serotonin 5-HT1F receptors may synergistically suppress CGRP signaling pathways. This approach enhances anti-migraine efficacy through peripheral restriction while circumventing central adverse effects (e.g., somnolence) mediated by 5-HT1F activation in the CNS. Here, we present a structure-based strategy to identify dual-target ligands for G-protein-coupled receptors. By integrating computational modeling and pharmacological screening, we designed compounds that simultaneously inhibit CGRP receptors and activate 5-HT1F receptors, demonstrating potent anti-migraine potential. Among these, compound 17a (PCC0105005) was found to be working at nanomolar concentrations at simultaneously influencing CGRP and 5-HT1f receptors. Pharmacokinetic profiling indicated rapid absorption, sustained plasma exposure, and limited brain penetration-mitigating CNS side effects while maintaining peripheral efficacy. In vivo, PCC0105005 significantly alleviated somatic and craniofacial allodynia symptoms by previously-validated Migraine Assessment Models Mechanistically, it suppressed CGRP synthesis and attenuated ERK/CREB phosphorylation, thereby linking migraine symptom with c-Fos activation-a key mediator of nociceptive sensitization. Collectively, these findings establish a preclinical foundation for elucidating dual-target CGRP antagonists/5-HT1F agonists with synergistic therapeutic strategies against migraine.