Cr. Baeza et al., ANALOGS OF GALANIN(1-16) MODIFIED IN POSITIONS 1-3 AS LIGANDS TO RAT HYPOTHALAMIC GALANIN RECEPTORS, Acta chemica Scandinavica, 48(5), 1994, pp. 434-438
Structure-activity relationship (SAR) studies have revealed that the f
irst three residues of galanin (Gly1-Trp2-Thr3) are of critical import
ance for high-affinity binding to the galanin receptor. Furthermore de
gradation studies have shown that galanin is easily cleaved to yield i
nactive fragments in rat hypothalamus (t1/2 = 100 min). To obtain gala
nin receptor ligands with long-lasting biological activity the amino-t
erminus of galanin must be protected. We have therefore synthesized an
alogs of rat galanin(1-16) carrying modifications at the three amino-t
ermini of galanin. All modifications of the peptide backbone flanking
Trp2 as in the analogs [N-Mc-Trp2]-galanin(1-16), [Tcc2]-galanin-(1-16
), (Trp2-PSI[CH2NH]-Thr3)-galanin-(1-16) produced a dramatic loss of a
ffinity toward the galanin receptor. [N-Me-Thr3]-galanin(1-16) was the
most active of the peptide backbone modified analogs (K(D) = 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 muM, did not displace [I-125]galanin binding. N-Methylation of
Gly1 by the introduction of sarcosine {[Sar1]-galanin(1-16)} did not s
ignificantly affect the ligand-binding properties of galanin(1-16) (K(
D) = 8.7 +/- 0.1 nM).