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J Med Chem. 1994 Jan 7;37(1):141-5.

Design of cyclic deltorphins and dermenkephalins with a disulfide bridge leads to analogues with high selectivity for delta-opioid receptors.

Author information

1
Department of Chemistry, University of Arizona, Tucson 85721.

Abstract

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 mu- and delta-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 delta-selective series of analogues, which fully confirmed our prediction. The cyclic analogues formula; see text: DT I are among the most delta-selective analogues described thus far.

PMID:
8289187
DOI:
10.1021/jm00027a017
[Indexed for MEDLINE]

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