Linear and cyclic N-terminal galanin fragments and analogs as ligands at the hypothalamic galanin receptor

The neuropeptide galanin (1–29) binds with high affinity to hypothalamic receptors (KD∼ 0.9 nM) and regulates feeding behavior. The N‐terminal fragments (1–16), (1–16)NH2 are high affinity (KD∼ 6nM) full agonists in vivo and in vitro.l‐Ala substitutions show that amino acid residues Gly1, Trp2, Asn5, Tyr9, and Gly12 are important for the high affinity binding of galanin (1–16). Shortening the fragment (1–16) to galanin (1–7) causes a gradual drop of affinity: galanin (1–15), (1–14), and (1–13) have submicromolar KD values and galanin (1–12) has KD∼ 3 μm. Cyclic analogs of galanin (1–12) of different ring size were synthesized by condensing Gly1 and Gly12 without or with spacer groups. These analogs, independent of ring size, had a lower affinity than the linear galanin (1–12). Derivatization of the N‐terminus of galanin (1–29), (1–16), and (1–12) all resulted in a large drop of affinity for the receptors, suggesting again the importance of the free N‐terminal Gly.