DESIGN OF CYCLIC DELTORPHINS AND DERMENKEPHALINS WITH A DISULFIDE BRIDGE LEADS TO ANALOGS WITH HIGH SELECTIVITY FOR DELTA-OPIOID RECEPTORS

We earlier suggested that the low receptor selectivity observed for pr eviously synthesized constrained analogues of deltorphin I (DT I) was the result of a reduction in the lipophilic surface of the C-terminal of the peptide. To confirm this prediction and to further test a previ ously proposed conformational model for bioactivity at delta opioid re ceptors, we have synthesized several new cyclic analogues with the gen eral structure [D-Xaa(2),Yaa(5)]deltorphin I and II in which Xaa(2) is D-cysteine or D-penicillamine (D-Pen), and Yaa(5) is an L- or D-penic illamine residue. Additional substitutions at positions 4, 6, and 7 al so were examined. The analogues were tested for binding to mu- and del ta-opioid receptors and in mouse vas deferens and guinea pig ileum bio logical assays. The introduction of a lipophilic L-Pen in position 5 a nd D-Cys or D-Pen in position 2 resulted in a highly delta-selective s eries of analogues, which fully confirmed our prediction. The cyclic a nalogues [D-Pen(2),Pen(5)]DTI and [D-Pen(2),Pen(5),Nle(6)]DTI are amon g the most delta-selective analogues described thus far.