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Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain.

Publication ,  Journal Article
Hughes, FM; Shaner, BE; Brower, JO; Woods, RJ; Dix, TA
Published in: Open Med Chem J
2013

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.

Duke Scholars

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Published In

Open Med Chem J

DOI

ISSN

1874-1045

Publication Date

2013

Volume

7

Start / End Page

16 / 22

Location

United Arab Emirates
 

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Hughes, F. M., Shaner, B. E., Brower, J. O., Woods, R. J., & Dix, T. A. (2013). Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain. Open Med Chem J, 7, 16–22. https://doi.org/10.2174/1874104501307010016
Hughes, Francis M., Brooke E. Shaner, Justin O. Brower, R Jeremy Woods, and Thomas A. Dix. “Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain.Open Med Chem J 7 (2013): 16–22. https://doi.org/10.2174/1874104501307010016.
Hughes FM, Shaner BE, Brower JO, Woods RJ, Dix TA. Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain. Open Med Chem J. 2013;7:16–22.
Hughes, Francis M., et al. “Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain.Open Med Chem J, vol. 7, 2013, pp. 16–22. Pubmed, doi:10.2174/1874104501307010016.
Hughes FM, Shaner BE, Brower JO, Woods RJ, Dix TA. Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain. Open Med Chem J. 2013;7:16–22.

Published In

Open Med Chem J

DOI

ISSN

1874-1045

Publication Date

2013

Volume

7

Start / End Page

16 / 22

Location

United Arab Emirates