Evaluation of truncated neuropeptide Y analogues with modifications of the tyrosine residue in position 1 on Y1, Y2 and Y3 receptor sub-types.

Substitutions of the tyrosine residue in position 1 of truncated neuropeptide Y (N-terminal fragment 1-4 linked to C-terminal fragment 18-36 by the epsilon-aminocaproic acid) produced analogues that compete for specific [125I]polypeptide YY (PYY) binding in the frontoparietal cortex (Y1-enriched) with a profile best fitted to a two site-model with KD values in the low and high nM range, respectively. In the hippocampal membrane preparations (Y2-enriched), halogen substitutions on the aromatic ring generated analogues with competition profiles best fitted to a one-site model, revealing differences between the two binding assays and the interaction of these analogues with the Y1 and Y2 receptor sub-types. In the rat vas deferens (Y2-enriched), all truncated analogues inhibited the twitch response with similar or slightly weaker potency than the native molecule. In contrast, these molecules were markedly less potent than neuropeptide Y (NPY) in the rabbit saphenous vein (Y1-enriched) and the rat distal colon (Y3-enriched). Some of the truncated analogues were inactive at up to microM concentrations in the rat distal colon, demonstrating the distinct structural requirement of the receptor sub-type present in this bioassay. These results revealed that amino acid residues between positions 5 and 17 are critical for the maintenance of optimal affinity for the NPY receptors present in the rabbit saphenous vein and the rat distal colon.(ABSTRACT TRUNCATED AT 250 WORDS)