Analogs of galanin (1-16) modified in positions 1-3 as ligands to rat hypothalamic galanin receptors.
Structure-activity relationship (SAR) studies have revealed that the first three residues of galanin (Gly1-Trp2-Thr3) are of critical importance for high-affinity binding to the galanin receptor. Furthermore degradation studies have shown that galanin is easily cleaved to yield inactive fragments in rat hypothalamus (t1/2 = 100 min). To obtain galanin receptor ligands with long-lasting biological activity the amino-terminus of galanin must be protected. We have therefore synthesized analogs of rat galanin(1-16) carrying modifications at the three amino-termini of galanin. All modifications of the peptide backbone flanking Trp2 as in the analogs [N-Me-Trp2]-galanin(1-16), [Tcc2]-galanin-(1-16), (Trp2-psi[CH2NH]-Thr3)-galanin-(1-16) produced a dramatic loss of affinity toward the galanin receptor. [N-Me-Thr3]-galanin(1-16) was the most active of the peptide backbone modified analogs (KD = 997 +/- 1 nM). Modifications of the indole ring in Trp2 ([For-Trp2]-galanin-(1-16), [Tcc2]-galanin-(1-16)) yielded analogs which, at concentrations up to 10 microM, did not displace [125I]galanin binding. N-Methylation of Gly1 by the introduction of sarcosine ([Sar1]-galanin(1-16)) did not significantly affect the ligand-binding properties of galanin(1-16) (KD = 8.7 +/- 0.1 nM).
Department of Neurochemistry and Neurotoxicology, Stockholm University, Sweden.
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Rivera Baeza
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Kask
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Langel
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Bartfai
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Undén
D000595:Amino Acid Sequence; D000818:Animals; D019004:Galanin; D007031:Hypothalamus / Q000378:metabolism / Q000648:ultrastructure*; D008745:Methylation; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D044088:Receptors, Galanin; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D013329:Structure-Activity Relationship
D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D044088:Receptors, Galanin; D011964:Receptors, Gastrointestinal Hormone; C062019:galanin (1-16); D019004:Galanin