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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 ¹H 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 …