AbstractAdrenomedullin (ADM) is a peptide hormone of the calcitonin gene‐related peptide (CGRP) family. It is involved in the regulation of cardiovascular processes such as angiogenesis, vasodilation, and the reduction of oxidative stress. ADM mediates its effects by activation of the ADM‐1 and ‐2 receptors (AM1R/AM2R), but also activates the CGRP receptor (CGRPR) with reduced potency. It binds to the extracellular domains of the receptors with its C‐terminal binding motif (residues 41–52). The activation motif, consisting of a disulfide‐bonded ring structure (residues 16–21) and an adjacent helix (residues 22–30), binds to the transmembrane region and stabilizes the receptor conformation in the active state. While it was shown that the binding motif of ADM guides AM1R selectivity, there is little information on the activation motif itself. Here, we demonstrate that Thr22 of ADM contributes to the selectivity. By using solid‐phase peptide synthesis and cAMP‐based signal transduction, we studied the effects of analogues in the activation motif of ADM on AM1R and CGRPR activity. Our results indicate that Thr22 terminates the α‐helix and orients the ring segment by hydrogen bonding. Using olefin stapling, we showed that the α‐helical arrangement of the ring segment leads to decreased AM1R activity, but does not affect CGRPR activation. These results demonstrate that the conformation of the ring segment of ADM has a strong impact on the selectivity within the receptor system.