Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception

Lohman, Rink-Jan, Harrison, Rosemary S., Ruiz-Gómez, Gloria, Hoang, Huy N., Shepherd, Nicholas E., Chow, Shiao, Hill, Timothy A., Madala, Praveen K. and Fairlie, David P. (2015) Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception. Vitamins and Hormones, 97 1-55. doi:10.1016/bs.vh.2014.10.001

Author Lohman, Rink-Jan
Harrison, Rosemary S.
Ruiz-Gómez, Gloria
Hoang, Huy N.
Shepherd, Nicholas E.
Chow, Shiao
Hill, Timothy A.
Madala, Praveen K.
Fairlie, David P.
Title Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception
Journal name Vitamins and Hormones   Check publisher's open access policy
ISSN 0083-6729
Publication date 2015-01-14
Sub-type Article (original research)
DOI 10.1016/bs.vh.2014.10.001
Open Access Status Not yet assessed
Volume 97
Start page 1
End page 55
Total pages 55
Place of publication Maryland Heights, MO United States
Publisher Academic Press
Language eng
Subject 1314 Physiology
1310 Endocrinology
Abstract Nociceptin (orphanin FQ) is a 17-residue neuropeptide hormone with roles in both nociception and analgesia. It is an opioid-like peptide that binds to and activates the G-protein-coupled receptor opioid receptor-like-1 (ORL-1, NOP, orphanin FQ receptor, kappa-type 3 opioid receptor) on central and peripheral nervous tissue, without activating classic delta-, kappa-, or mu-opioid receptors or being inhibited by the classic opioid antagonist naloxone. The three-dimensional structure of ORL-1 was recently published, and the activation mechanism is believed to involve capture by ORL-1 of the high-affinity binding, prohelical C-terminus. This likely anchors the receptor-activating N-terminus of nociception nearby for insertion in the membrane-spanning helices of ORL-1. In search of higher agonist potency, two lysine and two aspartate residues were strategically incorporated into the receptor-binding C-terminus of the nociceptin sequence and two Lys(i)→Asp(i+4) side chain-side chain condensations were used to generate lactam cross-links that constrained nociceptin into a highly stable α-helix in water. A cell-based assay was developed using natively expressed ORL-1 receptors on mouse neuroblastoma cells to measure phosphorylated ERK as a reporter of agonist-induced receptor activation and intracellular signaling. Agonist activity was increased up to 20-fold over native nociceptin using a combination of this helix-inducing strategy and other amino acid modifications. An NMR-derived three-dimensional solution structure is described for a potent ORL-1 agonist derived from nociceptin, along with structure-activity relationships leading to the most potent known α-helical ORL-1 agonist (EC 40pM, pERK, Neuro-2a cells) and antagonist (IC 7nM, pERK, Neuro-2a cells). These α-helix-constrained mimetics of nociceptin(1-17) had enhanced serum stability relative to unconstrained peptide analogues and nociceptin itself, were not cytotoxic, and displayed potent thermal analgesic and antianalgesic properties in rats (ED 70pmol, IC 10nmol, s.c.), suggesting promising uses in vivo for the treatment of pain and other ORL-1-mediated responses.
Keyword Agonist
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Created: Thu, 12 Apr 2018, 21:53:45 EST