In insects essential physiological processes such as muscle activity or water balance are controlled by neuropeptides. However, owing to their metabolic instability and adverse physicochemical properties peptides are unsuited as crop protection agents. Helicokinin I, a diuretic neuropeptide of cotton pest Helicoverpa zea represents a most promising tar- get for the design of neuropeptide mimetics. Several helicokinin analogues containing scaffolds with varying rigidity anddifferent orientations of the N- and C-terminal peptide chains were synthesized and tested for receptor binding. Additional conformational analyses by NMR spectroscopy in a mem- brane-mimicking environment together with MD simulations provide a deeper insight into the structural requirements for receptor binding and explain the remarkable activity of a macrocyclic helicokinin I derivative.