Development of a Peptide-Derived Orally-Active Kappa-Opioid Receptor Agonist Targeting Peripheral Pain

Francis M Hughes, Jr1, 2, 3, $, *, Brooke E Shaner1, Justin O Brower2, R. Jeremy Woods2, Thomas A Dix1, 2, 3
1 Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, 280 Calhoun Street, P. O. Box 250140, Charleston, SC 29425-2303, USA;
2 Argolyn Bioscience, Inc. 2530 Meridian Parkway, Suite 200, Durham, NC 27713, USA;
3 Halimed Pharmaceuticals Inc.,300 West Coleman Blvd. Suite 203, Mt. Pleasant, SC 29464, USA

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© Hughes et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Department of Urology, Medical University of South Carolina, 96 Jonathan Lucas St. CSB644, Charleston, SC 29425, USA; Tel: +1 (843) 792-6185; Fax +1 (843) 792-8523; E-mail:
$ Current address: Department of Urology, Medical University of South Carolina, 96 Jonathan Lucas St., CSB644, Charleston, SC 29425, USA


Kappa-opioid agonists are particularly efficacious in the treatment of peripheral pain but suffer from central nervous system (CNS)-mediated effects that limit their development. One promising kappa-agonist is the peptidic compound CR665. Although not orally available, CR665 given i.v. exhibits high peripheral to CNS selectivity and benefits patients with visceral and neuropathic pain. In this study we have generated a series of derivatives of CR665 and screened them for oral activity in the acetic acid-induced rat writhing assay for peripheral pain. Five compounds were further screened for specificity of activation of kappa receptors as well as agonism and antagonism at mu and delta receptors, which can lead to off-target effects. All active derivatives engaged the kappa receptor with EC50s in the low nM range while agonist selectivity for kappa over mu or delta was >11,000-200,000-fold. No antagonist activity was detected. One compound was chosen for further analysis (Compound 9). An oral dose response of 9 in rats yielded an EC50 of 4.7 mg/kg, approaching a druggable level for an oral analgesic. To assess the peripheral selectivity of this compound an i.v. dose response in rats was assessed in the writhing assay and hotplate assay (an assay of CNS-mediated pain). The EC50 in the writhing assay was 0.032 mg/kg while no activity was detectable in the hotplate assay at doses as high as 30 mg/kg, indicating a peripheral selectivity of >900-fold. We propose that compound 9 is a candidate for development as an orally-available peripherally-restricted kappa agonist.

Keywords: Agonist, analgesic, kappa, neurotensin, opioid, pain, peripheral.