Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-dehydro-(S)-proline (Delta(3)Pro), azetidine-3-carboxylic acid (3Aze) and dehydro-alanine (Delta Ala) have been used to prepare [Delta(3)Pro(2)]EM-2 (1), [Aze(2)]EM-1 (2), [Aze(2)]EM-2 (3), [3Aze(2)]EM-1 (4), [3Aze(2)]EM-2 (5) and [Delta Ala(2)]EM-2 (6). Binding assays and functional bioactivities for mu-and delta-receptors are reported. The highest affinity, bioactivity and selectivity are shown by peptides 2 and 3 containing the Aze residue. (C) 2009 Elsevier Ltd. All rights reserved.