Stabilization of β-turn conformations in enkephalins α-Aminoisobutyric acid analogs

Stereochemical constraints have been introduced into the enkephalin backbone by substituting &#945;-aminoisobutyryl (Aib) residues at positions 2 and 3, instead of Gly. <SUP>1</SUP>H n.m.r. studies of Tyr-Aib-Gly-Phe-Met-NH<SUB>2</SUB>, Tyr-Aib-Aib-Phe-Met-NH<SUB>2</SUB> and Tyr-Gly-Aib-Phe-Met-NH<SUB>2</SUB> demonstrate the occurrence of folded, intramolecularly hydrogen bonded structures in organic solvents. Similar conformations are also favoured in the corresponding t-butyloxycarbonyl protected tetrapeptides, which lack the Tyr residue. A &#946;-turn centred at positions 2 and 3 is proposed for the Aib<SUP>2</SUP>-Gly<SUP>3</SUP> analog. In the Gly<SUP>2</SUP>-Aib<SUP>3</SUP> analog, the &#946;-turn has Aib<SUP>3</SUP>-Phe<SUP>4</SUP> as the corner residues. The Aib<SUP>2</SUP>-Aib<SUP>3</SUP> analog adopts a consecutive &#946;-turn or 3<SUB>10</SUB> helical conformation. High in vivo biological activity is observed for the Aib<SUP>2</SUP> and Aib<SUP>2</SUP>-Aib<SUP>3</SUP> analogs, while the Aib<SUP>3</SUP> peptide is significantly less active