Novel helix-constrained nociceptin derivatives are potent agonists and antagonists of ERK phosphorylation and thermal analgesia in mice.
The nociceptin opioid peptide receptor (NOP, NOR, ORL-1) is a GPCR that recognizes nociceptin, a 17-residue peptide hormone. Nociceptin regulates pain transmission, learning, memory, anxiety, locomotion, cardiovascular and respiratory stress, food intake, and immunity. Nociceptin was constrained using an optimized helix-inducing cyclization strategy to produce the most potent NOP agonist (EC50 = 40 pM) and antagonist (IC50 = 7.5 nM) known. Alpha helical structures were measured in water by CD and 2D (1)H NMR spectroscopy. Agonist and antagonist potencies, evaluated by ERK phosphorylation in mouse neuroblastoma cells natively expressing NOR, increased 20-fold and 5-fold, respectively, over nociceptin. Helix-constrained peptides with key amino acid substitutions had much higher in vitro activity, serum stability, and thermal analgesic activity in mice, without cytotoxicity. The most potent agonist increased hot plate contact time from seconds up to 60 min; the antagonist prevented this effect. Such helix-constrained peptides may be valuable physiological probes and therapeutics for treating some forms of pain.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Rosemary S
RS
Harrison
Gloria
G
Ruiz-Gómez
Timothy A
TA
Hill
Shiao Y
SY
Chow
Nicholas E
NE
Shepherd
Rink-Jan
RJ
Lohman
Giovanni
G
Abbenante
Huy N
HN
Hoang
David P
DP
Fairlie
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018847:Opioid Peptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects*; D013696:Temperature; D000097629:Nociceptin
D000700:Analgesics; D048049:Extracellular Signal-Regulated MAP Kinases; D018847:Opioid Peptides; D000097629:Nociceptin