Bioorganic & Medicinal Chemistry Letters 2009-08-01

Synthesis and evaluation of new endomorphin analogues modified at the Pro(2) residue.

Domenica Torino, Adriano Mollica, Francesco Pinnen, Gino Lucente, Federica Feliciani, Peg Davis, Josephine Lai, Shou-Wu Ma, Frank Porreca, Victor J Hruby

Index: Bioorg. Med. Chem. Lett. 19 , 4115-8, (2009)

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Abstract

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 (DeltaAla) 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 [DeltaAla(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.