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Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

Söll, Richard M., Dinger, Michaela C., Lundell, Ingrid, Larhammer, Dan, Beck‐Sickinger, Annette G.
European journal of biochemistry 2001 v.268 no.10 pp. 2828-2837
agonists, amino acids, antagonists, brain, humans, neuropeptide Y, swine
Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian brain and acts in humans via at least three receptor subtypes: Y1, Y2, and Y5. Whereas selective agonists and antagonists are known for the Y2‐ and Y5‐receptors, the Y1‐receptor still lacks a highly selective agonist. This work presents the first NPY‐based analogues with Y1‐receptor preference and agonistic properties. Furthermore, the importance of specific amino acids of NPY for binding to the Y‐receptor subtypes is presented. Amongst the analogues tested, [Phe7,Pro34]pNPY (where pNPY is porcine neuropeptide Y) showed the most significant Y1‐receptor preference (> 1 : 3000‐fold), with subnanomolar affinity to the Y1‐receptor, and Ki values of ≈ 30 nm for the Y2‐ and Y5‐subtype, respectively. Variations of position 6, especially [Arg6,Pro34]pNPY and variations within positions 20–23 of NPY were found to result in further analogues with significant Y1‐receptor preference (1 : 400–1 : 2000). In contrast, cyclo S–S [Cys20,Cys24]pNPY was found to be a highly selective ligand at the Y2‐receptor, binding only threefold less efficiently than NPY. Analogues containing variations of positions 31 and 32 showed highly reduced affinity to the Y1‐receptor, while binding to the Y5‐receptor was affected less. Inhibition of cAMP‐accumulation of selected peptides with replacements within position 20–23 of NPY showed preserved agonistic properties. The NPY analogues tested give insights into ligand–receptor interaction of NPY at the Y1‐, Y2‐ and Y5‐receptor and contribute to our understanding of subtype selectivity. Furthermore, the Y1‐receptor‐preferring peptides are novel tools that will provide insight into the physiological role of the Y1‐receptor.