The neuropeptide galanin (1-29) binds with high affinity to hypothalamic receptors (K, z 0 . 9 1~) and regulates feeding behavior. The N-terminal fragments (l-l6), (I-16)NH2 are high affinity (K, z 6 n~) full agonists in vivo and in vitro. L-Ala substitutions show that amino acid residues Gly', Trp', Asn', Tyr', and Glyl'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 (I-IS), (l-l4), and (1-13) have submicromolar K, values and galanin (1-12) has K, z 3 p M . Cyclic analogs of galanin (1-12) of different ring size were synthesized by condensing Gly' and Gly" 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. K c j word.?: galanin fragments and analogs; receptor binding; solid phase synthesis; structure-activity relationship Galanin, a 29 amino acid long C-terminally amidated gut and brain peptide (I), possesses several important biological activities; galanin is a potent inhibitor of the glucose induced insulin release in dog (2), it inhibits acetylcholine release in the rat ventral hippocampus (3) and stimulates the release of human growth hormone (4), furthermore, it potentiates the effects of morphine on suppression of the spinal flexor reflex (9, and potently stimulates feeding behavior when injected into the hypothalamus or the lateral ventricles (6).The amino acid sequence of galanin is known from three species: porcine (1). rat (7), and bovine (8). These available amino acid sequences (Fig. I ) show a complete conservation of the first 15 amino acids in the N-terminal portion of galanin, while amino acid substitutions occur (in residues 23, 26, and 29) in the C-terminal portion of the three sequences.Studies with galanin (1-15) (9) and porcine galanin