Topographical requirements for delta opioid ligands: presence of a carboxyl group in position 4 is not critical for deltorphin high delta receptor affinity and analgesic activity.
To investigate the role of the carboxyl group in deltorphin molecules, we have synthesized three new analogues in which the acidic amino acid residues in position 4 of the deltorphins were replaced by non-acidic but hydrophilic amino acids residues. The three analogues, [Ser4]-, [Gln4]-, and [Cys4]-deltorphin, all are as potent or more potent than either deltorphin I or II at delta opioid receptors and possess good delta selectivities. The excellent correlation between their in vitro delta receptor potencies and their intrathecal antinociception activity forms a strong argument for involvement of those receptors in spinal nociceptive modulation in the rats.
Misicka
A
A
Department of Chemistry, University of Arizona, Tucson 85721.
Lipkowski
A W
AW
Fang
L
L
Knapp
R J
RJ
Davis
P
P
Kramer
T
T
Burks
T F
TF
Yamamura
H I
HI
Carr
D B
DB
Hruby
V J
VJ
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry*; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010146:Pain; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017465:Receptors, Opioid, delta
D000700:Analgesics; D009842:Oligopeptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C060208:deltorphin I, Ala(2)-; C060209:deltorphin II, Ala(2)-