Many peptides that activate class B1 GPCRs, such as the glucagon receptor (GCGR) or the parathyroid hormone receptor-1 (PTH1R4), are α-helical in the active receptor-bound form. Now, despite destabilizing the helical conformation of parent glucagon and PTH agonists, the presented design strategy generates potent and biased heterochiral analogues by replacing select l-α-amino-acid residues with d-α-amino acids.