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Novel analogues of neuropeptide Y with a preference for the Y1âreceptor
- SÃ¶ll, Richard M., Dinger, Michaela C., Lundell, Ingrid, Larhammer, Dan, BeckâSickinger, Annette G.
- European journal of biochemistry 2001 v.268 no.10 pp. 2828-2837
- agonists, amino acids, antagonists, brain, humans, neuropeptide Y, swine
- NeuropeptideâY (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 Y2â and Y5âreceptors, the Y1âreceptor still lacks a highly selective agonist. This work presents the first NPYâbased analogues with Y1âreceptor preference and agonistic properties. Furthermore, the importance of specific amino acids of NPY for binding to the Yâreceptor subtypes is presented. Amongst the analogues tested, [Phe7,Pro34]pNPY (where pNPY is porcine neuropeptide Y) showed the most significant Y1âreceptor preference (>â1â:â3000âfold), with subnanomolar affinity to the Y1âreceptor, and Ki values of ââ30ânm for the Y2â and Y5âsubtype, respectively. Variations of position 6, especially [Arg6,Pro34]pNPY and variations within positions 20â23 of NPY were found to result in further analogues with significant Y1âreceptor preference (1â:â400â1â:â2000). In contrast, cyclo SâS [Cys20,Cys24]pNPY was found to be a highly selective ligand at the Y2âreceptor, binding only threefold less efficiently than NPY. Analogues containing variations of positions 31 and 32 showed highly reduced affinity to the Y1âreceptor, while binding to the Y5âreceptor was affected less. Inhibition of cAMPâaccumulation of selected peptides with replacements within position 20â23 of NPY showed preserved agonistic properties. The NPY analogues tested give insights into ligandâreceptor interaction of NPY at the Y1â, Y2â and Y5âreceptor and contribute to our understanding of subtype selectivity. Furthermore, the Y1âreceptorâpreferring peptides are novel tools that will provide insight into the physiological role of the Y1âreceptor.