We earlier suggested that the low receptor selectivity observed for previously 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 previously proposed conformational model for bioactivity at delta opioid receptors, we have synthesized several new cyclic analogues with the general structure [D-Xaa2,Yaa5] deltorphin I and II in which Xaa2 is D-cysteine or D-penicillamine (D-Pen), and Yaa5 is an L- or D-penicillamine residue. Additional substitutions at positions 4, 6, and 7 also were examined. The analogues were tested for binding to μ- and δ-opioid receptors and in mouse vas deferens and guinea pig ileum biological assays. The introduction of a lipophilic L-Pen in position 5 and D-Cys or D-Pen in position 2 resulted in a highly δ-selective series of analogues, which fully confirmed our prediction. The cyclic analogues [D-Pen2,Pen5]DT I and [D-Pen2,Pen5,Nle6]DT I are among the most δ-selective analogues described thus far.
|Original language||English (US)|
|Number of pages||5|
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 1994|
ASJC Scopus subject areas
- Organic Chemistry