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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis, Conformational Analysis, and Biological Activity of[Aza-3-indoylgly 4 ] GHRP-6 as an Aza-Tryptophan Analog ofGrowth Hormone Releasing Peptide-6Caroline Proulx 1 , David Sabatino 1 , Petra Pohankova 2 , Huy Ong 2 ,and William D. Lubell 11 Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville,Montréal, Québec, H3C 3J7, Canada; 2 Faculté de Pharmacie, Université de Montréal,C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, CanadaIntroductionPeptide mimics in which the alpha-carbon of one or more amino acid residues has beensubstituted by a nitrogen atom are called azapeptides [1]. The carbon to nitrogenexchange may induce -turn formation by constraining both the phi ( ) and psi ( )dihedral angles, as respective consequences of the lone pair-lone pair repulsion betweenthe two adjacent nitrogen atoms and replacement of an amide bond by urea functionality[2]. The aza-phenylalanine 4 analog of growth hormone releasing peptide-6 (GHRP-6,His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 ) has shown selectivity for the CD36 over the GHS-R1a receptor. In an effort towards better mimicking the Trp 4 residue while preserving theconformational bias induced by the aza-amino acid, the syntheses of [azaTrp 4 ]- and [aza-3-indoylgly 4 ]GHRP-6 were pursued [3,4].Results and DiscussionAttempts to synthesize azaTrp-containing peptide met with loss of the indolylmethylmoiety upon treating the resin with TFA during resin cleavage [4]. On the other hand,[azaPhe 4 ]GHRP-6 was stable and displayed a circular dichroism (CD) signature in water,which was characteristic of a turn, in contrast to the random coil CD curve displayed bythe parent sequence (Figure 1) [5]. Moreover, relative to GHRP-6, [azaPhe 4 ]GHRP-6maintained affinity to the CD36 receptor, with a 1000 fold loss of affinity towards theGHS-R1a receptor. The synthesis of [aza-3-indoylgly 4 ]GHRP-6 (6) was accomplished bysubmonomer azapeptide synthesis [5], featuring regioselective N-arylation of resin-boundsemicarbazone 3 with N-Boc-3-iodoindole (Scheme 1) [3]. Tolerant to the acidicconditions used for resin cleavage, the aza-3-indoylglycine residue may serve as a stableazaTrp surrogate.Scheme 1. Synthesis of [aza-3-indoylgly 4 ]GHRP-6.458