α-Helical small molecular size analogues of neuropeptide Y: Structure-activity relationships

C‐terminal analogues of neuropeptide Y (NPY) of small molecular size have been synthesized. The influence of chain length, single or multiple amino acid substitution, and segment substitutions on receptor binding, pre‐ and postsynaptic biological activity, and conformational properties have been investigated. Receptor binding and in vivo assays revealed biological activity for NPY Ac‐25‐36 that increased with increasing α‐helicity. In attempts to stabilize the α‐helical content, three independent types of modified NPY Ac‐25‐36 analogues were synthesized. Strong agonistic activities could be detected in a series of discontinuous analogues, which are constructs of N‐terminal parts linked via different spacer molecules to C‐terminal segments. One of the most active molecules was NPY 1‐4‐Aca‐25‐36 (Aca, ε‐aminocaproic acid). For the first time conformational properties of a series of small NPY analogues have been investigated by CD, and correlated with biological activity and receptor binding. A C‐terminal dodecapeptide segment of NPY with an amount of 50% substitution to the native C‐terminal sequence of NPY was found to exhibit significant receptor binding.