Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, including peptides from sand fly saliva. We found modifications which improved the metabolic stability of these peptides in vitro and in vivo. More detailed SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the in vitro PAC1R inhibitory activity of the analogs to the pM IC90 range . Lead peptide analogs with robust in vivo efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model will be discussed. The first co-crystal structure of a PAC1R antagonist peptide with PAC1R extracellular domain will also be presented.