Targeting amylin (Amy) receptors (AMYRs) can reduce body weight with additional benefits to other anti-obesity treatments such as glucagon-like peptide-1 receptor (GLP-1R) agonists. AMYRs are heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), yielding AMY1R, AMY2R and AMY3R, respectively. A hallmark of AMYR activation by Amy is the formation of a secondary structural motif, termed a “bypass motif” (residues S19-P25) that partly contributes to selective activation of cAMP responses at AMYRs over CTR. This study explored the feasibility of tuning the selectivity of Amy analogues by modifying the residues (19-22) located within the bypass motif, resulting in a selective AMYR agonist, San385, as well as a series of non-selective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMY3R, as well as San45-bound AMY3R and CTR, decoding the structure-activity relationship (SAR) of these peptides. In particular, San45 is conjugated at position 19 with a lipid modification that anchors the peptide at the edge of receptor bundle and enables an alternate binding mode when bound to the CTR, in addition to the bypass mode of binding to AMY3R. This unique mechanism provides a single intervention strategy through targeted lipid modification to the structure-based design of long-acting, non-selective, Amy-based DACRAs with potential anti-obesity effects.