Structure-activity studies on high affinity NOP-active hexapeptides.
Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G-protein coupled receptor ORL1 (NOP), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiologic functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited number of high-affinity ligands to NOP, and particularly the lack of availability of useful specific antagonists. Herein, we describe the pharmacologic activity of a series of modified amino acid containing modifications of the hexapeptide Ac-RYYRWR-NH2, with high affinity for NOP. These compounds were tested for binding affinity using [3H]N/OFQ binding to human NOP in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS-binding in CHO cell membranes. These studies suggest that each Arg of the hexapeptide is required to maintain high-binding affinity. The peptide maintains high affinity if the Tyr2 or Tyr3 are modified, but at least one of these residues must maintain its hydroxyl group or there is a large decrease in intrinsic activity of the peptide.
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A K
AK
Judd
D J
DJ
Tuttle
R W
RW
Jones
A
A
Sanchez
W
W
Polgar
I
I
Berzetei-Gurske
L
L
Toll
D000818:Animals; D001120:Arginine / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D001120:Arginine; D018076:DNA, Complementary; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008024:Ligands; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D011994:Recombinant Proteins; D014443:Tyrosine; D000094942:Nociceptin Receptor; D000097629:Nociceptin