CONSTRAINED LINEAR OPIOID PEPTIDES. Jeffrey R. Deschamps, Clifford George, Christi Moore, Robert Cudney*, and Judith L. Flippen-Anderson, Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC, 20375 and *Hampton Research, Laguna Hills, CA.

A new class of potent site selective opioid peptides has been developed which consist entirely of aromatic amino acids and contain a conformationally restricted phenylalanine residue (i.e. tetrahydroisoquinoline-3-carboxylic acid, Tic) in position 2¹. More recent work on these short linear peptides has shown that aromaticity of residues 3 and 4 is not required for high binding affinity². Members of this family that contain a L-Tic residue in position 2 are ( selective antagonists and those that contain a D-Tic at position 2 are agonists with some preference for u receptors. Even the dipeptide (Tyr-Tic-NH₂) has been shown to possess substantial opioid activity³. We have determined the structures of several members of this new class of opioid peptides. A comparison of these structures reveals a relationship between the positions of the Tyr¹ and Tic² side chains and the activity of the peptide ligand. In TIPP (Tyr-Tic-Phe-Phe), a highly ( selective antagonist, the distance between these side chains is 5.9Å; in the agonist D-TIPP (Tyr-D-Tic-Phe-Phe) the distance between these side chains is approximately 6.5Å. Shorter ring-ring distances are associated with a conformation of enkephalin thought to represent that of an antagonist, while longer ring-ring distances are associated with a conformation which is thought to be required for agonist activity.

1. P.W. Schiller, et al. (1992) Proc. Nat. Acad. Sci., 89, 11871-11875.

2. H.I. Mosberg, et al. (1994) Lett. Pep. Sci., 1, 69-72.

3. P.A. Temussi , et al. (1994) Biochem Biophys Res. Comm., 198, 933-939.