作者
Rosemary S Harrison, Gloria Ruiz-Gomez, Timothy A Hill, Shiao Y Chow, Nicholas E Shepherd, Rink-Jan Lohman, Giovanni Abbenante, Huy N Hoang, David P Fairlie
发表日期
2010/12/9
期刊
Journal of medicinal chemistry
卷号
53
期号
23
页码范围
8400-8408
出版商
American Chemical Society
简介
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 …
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RS Harrison, G Ruiz-Gomez, TA Hill, SY Chow… - Journal of medicinal chemistry, 2010