Structure/activity relationships of C‐terminal neuropeptide Y peptide segments and analogues composed of sequence 1–4 linked to 25–36

C‐terminal analogues of neuropeptide Y have been synthesized. The influence of chain length, single‐amino‐acid substitutions and segment substitutions on receptor binding, biological activity and conformational properties has been investigated. Receptor binding and in vivo assays revealed biological activity already for amino acids 28–36 of neuropeptide Y [neuropeptide Y‐(Ac‐28–36)‐peptide] which increased with increasing chain length. Replacement of Arg 25 in neuropeptide Y‐(Ac‐25–36)‐peptide had no influence on binding, whereas Arg 33 and Arg 35 cannot be replaced by lysine or ornithine without considerable decrease in receptor binding. The introduction of conformational constraints by the 2‐aminoisobutyric acid residue (Aib) in position 30 and replacing the amino acids 28–32 by Ala‐Aib‐Ala‐Aib‐Ala decreased receptor binding. However, the corresponding Aib‐Ala‐Aib‐Ala‐Aib‐substituted analogue and a more flexible analogue with Gly 5 at position 28–32 exhibited considerable affinity for the receptor. All these substitutions led to a decrease in postsynaptic activity. Strong agonistic activities could be detected in a series of 10 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 neuropeptide Y amino acids 1–4 linked to amino acids 25–36 through aminohexanoic acid (Ahx) [neuropeptide Y‐(1–4‐Ahx‐25–36)‐peptide].