From structural evolution to an AI-driven future of 5-HT1F receptor agonists for migraine therapy.

Migraine is a prevalent and disabling neurological disorder that imposes a substantial global disease burden, particularly among women of childbearing age. Although therapies targeting the calcitonin gene-related peptide (CGRP) pathway have improved migraine management, a considerable proportion of patients exhibit an insufficient clinical response, highlighting the importance of CGRP-independent mechanisms. The 5-hydroxytryptamine 1F (5-HT1F) receptor, expressed in trigeminal neurons and involved in trigeminovascular signaling without vasoconstriction, represents a promising therapeutic target. The clinical approval of lasmiditan has validated the therapeutic potential of 5-HT1F agonism, although its association with central nervous system adverse effects underscores the need for safer and more selective ligands. This review integrates current understanding of the role of 5-HT1F receptor in migraine and systematically traces the structural evolution of small-molecule agonists, from early indole-based scaffolds through to simplified and clinically relevant chemotypes, while emphasizing conserved pharmacophoric features and geometric determinants of selectivity. We further discuss how artificial intelligence (AI)-driven approaches, including structure-aware generative modeling and knowledge-guided design, offer a strategic pathway to address the ligand-scarcity challenge of this low-data GPCR, potentially accelerating the discovery of next-generation 5-HT1F receptor agonists with optimized safety and efficacy. Collectively, this work links biological insight, medicinal chemistry evolution, and emerging computational tools to inform the development of improved antimigraine therapies.