Iminium cations are key to a plethora of chemical reactions, such as Mannich¹ and Pictet-Spengler reactions, amongst many others.² Since they are involved in the build-up of many heterocyclic scaffolds, iminium chemistry can also give access to novel, covalently constrained amino acids or dipeptides. In previous work,³ our research group investigated paths towards diverse isoquinoline and azepinone building blocks to access various types of conformationally restricted residues. Here, the (N-acyl)iminium ion serves as a precursor of the eventual cycles, which are formed via intramolecular electrophilic aromatic substitutions (EAS; see figure below). In order to reach the desired synthetic educts, different unnatural amino acids with varying (hetero)aromatic moieties were first synthesized using electrocatalysis⁴ and Negishi reactions.⁵ Depending on the nature of the aromatic moiety involved and the ring size targeted, some cyclizations proved more challenging than others. To guide the synthetic efforts, density functional theory (DFT) calculations were carried out to correlate theoretical activation energies and experimental outcomes. As a case study, the pharmacological impact of selected constrained residues encompassed within opioid peptides,⁶ but also hybrid opioid-non-opioid peptidomimetics,^7,8,9 will be presented, including effects on signaling efficacy and bias.