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      Targeting peripheral κ-opioid receptors for the non-addictive treatment of pain

      , * , 1 , 1 , 2

      Future Drug Discovery

      Newlands Press Ltd

      analgesic, kappa, opioid, pain, peripheral

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          Drug addiction to prescription μ-opioid agonists used in the setting of pain is a major public health threat, affecting millions of Americans. κ-opioid agonists (KOAs) may serve as a possible solution. KOAs have demonstrated indistinguishable analgesic activity relative to μ-opioid agonists in models of acute and chronic pain; however, conventional KOAs suffer from central nervous system (CNS)-mediated psychoactive side-effects. In this review, we discuss our efforts, as well as other's efforts, in developing peripherally restricted KOAs with retained or improved efficacy in rodent models of pain. Results indicate that our lead compound, JT09, acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated side-effects. In this review, we discuss our former results and future directions.

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          Most cited references 17

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          ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization.

          Selective PCR amplification of human and mouse genomic DNAs with oligonucleotides encoding highly conserved regions of the delta-opioid and somatostatin receptors generated a human DNA probe (hOP01, 761 bp) and its murine counterpart (mOP86, 447 bp). hOP01 was used to screen a cDNA library from human brainstem. A clone (named hORL1) was isolated, sequenced and found to encode a protein of 370 amino acids whose primary structure displays the seven putative membrane-spanning domains of a G protein-coupled membrane receptor. The hORL1 receptor is most closely related to opioid receptors not only on structural (sequence) but also on functional grounds: hORL1 is 49-50% identical to the murine mu-, delta- and kappa-opioid receptors and, in CHO-K1 cells stably transfected with a pRc/CMV:hORL1 construct, ORL1 mediates inhibition of adenylyl cyclase by etorphine, a 'universal' (nonselective) opiate agonist. Yet, hORL1 appears not to be a typical opioid receptor. Neither is it a somatostatin or sigma (N-allylnormetazocine) receptor. mRNAs hybridizing with synthetic oligonucleotides complementary to mOP86 are present in many regions of the mouse brain and spinal cord, particularly in limbic (amygdala, hippocampus, septum, habenula, ...) and hypothalamic structures. We conclude that the hORL1 receptor is a new member of the opioid receptor family with a potential role in modulating a number of brain functions, including instinctive behaviours and emotions.
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            Peripheral kappa-opioid agonists for visceral pain.

             P Riviere (2004)
            Kappa (kappa)-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain. Their analgesic effects are mediated in the periphery. The molecular targets involved include peripherally located kappa-receptors and possibly, at least for some nonpeptidic kappa-agonists, additional nonopioid molecular targets such as sodium channels located on primary sensory afferents. Overall, these properties are expected to be of therapeutic interest in various visceral pain conditions, including abdominal surgery associated with postoperative pain and ileus, pancreatitis pain, dysmenorrhea, labor pain and functional disorders such as irritable bowel syndrome or dyspepsia. The first kappa-agonists to be developed were brain-penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to kappa-receptors located behind the blood-brain barrier. New drug discovery programs are now geared towards the design of peripherally-selective kappa-agonists. So far, most of the organic molecule-based peripheral kappa-agonists have achieved limited peripheral selectivity and a practically insufficient therapeutic window to justify full development. These compounds have been used in a small number of clinical pilot studies involving visceral pain. Although encouraging, the clinical data available so far with this class of compounds are too limited and fragmented to fully validate the therapeutic utility of kappa-agonists in visceral pain. Additional clinical studies with safer kappa-agonists (i.e. with higher peripheral selectivity) are still required. The most suitable tools to address this question in the future appear to be the newly discovered class of tetrapeptide-based kappa-agonists, which have shown unprecedented levels of peripheral selectivity.
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              The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability.

               Ann Lin,  Mei-Chuan Ko (2013)
              Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans.

                Author and article information

                Future Drug Discovery
                Future Drug. Discov.
                Future Drug Discovery
                Newlands Press Ltd (London, UK )
                02 September 2019
                October 2019
                : 1
                : 2
                1Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina Campus, 280 Calhoun Street, PO Box 250140, Charleston, SC 29424-2303, USA
                2JT Pharmaceuticals, Inc., 300 West Coleman Blvd, Suite 203, Mount Pleasant, SC 29464-2303, USA
                Author notes
                [* ]Author for correspondence: Tel.: +1 843 876 5092; beckt@
                © 2019 Thomas A Dix

                This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License

                Page count
                Pages: 6


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