Design of cyclic deltorphins and dermenkephalins with a disulfide bridge leads to analogues with high selectivity for delta-opioid receptors.
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.
Misicka
A
A
Department of Chemistry, University of Arizona, Tucson 85721.
Lipkowski
A W
AW
Horvath
R
R
Davis
P
P
Yamamura
H I
HI
Porreca
F
F
Hruby
V J
VJ
D000595:Amino Acid Sequence; D000818:Animals; D003500:Cyclization; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin