The Phe sidechain in dermorphin was fixed into the trans conformation by linking the aromatic ring to the Gly nitrogen through a methylene bridge. The compound has high μ and δ-opioid activities. The naturally occurring peptides dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 1 and deltorphin (e.g. deltorphin II : H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 2) display different selectivities towards the opioid receptor subtypes. Whereas 1 is μ-selective, 2 is δ-selective, which is in agreement with the hypothesis of a common N-terminal "message" part, and a different C-terminal "address" part (1), the latter being responsible for the receptor selection. On the other hand, the importance of the relative orientation of the Tyr and Phe sidechains for determining receptor selectivity and affinity has been emphasized in several studies of opioid peptides containing Phe at positions 3 or 4 (2-6). For linear peptides such as 1 or 2, the flexibility of the backbone and especially of the sidechain moieties makes determination of the important conformational features responsible for biological activity very difficult. Therefore conformational flexibility has been reduced by cyclization of the peptide backbone (7). Alternatively, the sidechain orientation can be fixed by cyclization as has been done for Phe or Tyr by using a tetrahydroisoquinoline-3-carboxylic acid (Tic) structure (4,8,9). The use of Tic constrains the sidechain to the gauche(-) (χ1= -60°) or gauche(+) (χ1= +60°) staggered conformations (8). We now report fixing the Phe sidechain in 1 into the trans (χ1= 180°) conformation. This can be achieved by bridging the phenyl ring of Phe and the nitrogen atom of the succeeding amino acid by a methylene group (Fig. 1).