scholarly journals Tackling the opioid crisis - development of kappa-opioid receptor peptide agonists for safer analgesic therapy

2021 ◽  
Author(s):  
Rink-Jan Lohman ◽  
Karnaker Reddy Tupally ◽  
Ajit Kandale ◽  
Peter Cabot ◽  
Harendra Parekh
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Specific Activity ◽  
Opioid Analgesic ◽  
Kappa Opioid Receptor ◽  
Metabolic Stability ◽  
Clinical Translation ◽  
Kappa Opioid

The kappa opioid receptor (KOPr) has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side effects have the limited their clinical translation. Here, we modify an active endogenous Dynorphin peptide with the aim of improving drug-likeness and developing safer KOPr agonists for clinical use. Using rational, iterative design and modern peptide chemistry, we developed a series of potent, selective and metabolically stable peptides from Dynorphin 1-7. Peptides were assessed for cAMP-modulation against Kappa, Mu and Delta opioid receptors, metabolic stability, KOPr specificity and binding, and interrogated for in vitro desensitisation and pERK signalling capability. Finally, lead peptides were evaluated for efficacy in Freund’s complete adjuvant rat model of inflammatory nociception. A library of 70 peptides was synthesised and assessed for pharmacological and metabolic stability factors. At least 10 peptide candidates showed low nanomolar activity (˂50 nM) in a cAMP assay, specificity for KORr, and plasma half-life >60 min, with 6 candidates also stable in trypsin. None of the selected peptides showed pERK activity, with a bias towards cAMP signalling. In vivo, KA305 and KA311 showed anti-nociception opioid receptor-specific activity comparable to morphine and U50 844. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are biased peptide KOPr agonists, it is plausible they lack many of the most significant side effects, such as tolerance, addiction, sedation and euphoria/dysphoria, common to opioid analgesics.

Signaling Properties of Structurally Diverse Kappa Opioid Receptor Ligands: Toward in Vitro Models of in Vivo Responses

2019 ◽  
Vol 10 (8) ◽  
pp. 3590-3600 ◽  
Author(s):  
Amelia D. Dunn ◽  
Brian Reed ◽  
Jose Erazo ◽  
Ariel Ben-Ezra ◽  
Mary Jeanne Kreek
Keyword(s):  
Opioid Receptor ◽  
In Vitro Models ◽  
Kappa Opioid Receptor ◽  
Receptor Ligands ◽  
Kappa Opioid ◽  
Opioid Receptor Ligands

scholarly journals Kappa opioid receptor (KOR) signaling on peripheral sensory neurons in vitro and in vivo

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Matthew Rowan ◽  
Teresa Sanchez ◽  
Yamille Silva ◽  
Blaine McGuire ◽  
William Clarke ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Sensory Neurons ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

scholarly journals Nitric Oxide Stimulates Acute Pancreatitis Pain via Activating the NF-κB Signaling Pathway and Inhibiting the Kappa Opioid Receptor

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Mengwen Xue ◽  
Liang Han ◽  
Weikun Qian ◽  
Jie Li ◽  
Tao Qin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Pancreatitis ◽  
Opioid Receptor ◽  
Pain Treatment ◽  
Kappa Opioid Receptor ◽  
Clinical Feature ◽  
Kappa Opioid ◽  
No Donor

Pain is the most important clinical feature of acute pancreatitis (AP); however, its specific mechanism is currently unclear. In this study, we showed that AP caused an increase in nitric oxide (NO) secretion, activated the NF-κB pathway in the dorsal root ganglia (DRGs), and caused pain. We established an AP model in vivo and tested the expression of NO, the kappa opioid receptor (KOR), and pain factors. We showed that NO in AP was significantly elevated and increased the expression of pain factors. Next, by treating DRGs in vitro, it was found that NO activated the NF-κB pathway; conversely, NF-κB had no effect on NO. Moreover, inhibition of NF-κB promoted the KOR, whereas NF-κB did not change after KOR activation. Finally, behavioral experiments showed that a NO donor increased the pain behavior of mice, while a NO scavenger, NF-κB inhibitor, or KOR agonist attenuated the pain response in mice. These results suggest that iNOS/NO/NF-κB/KOR may be a key mechanism of pain in AP, providing a theoretical basis for the use of peripheral-restricted KOR agonists for pain treatment in AP.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

scholarly journals A45 A NOVEL PH-SENSITIVE OPIOID ANALGESIC THAT SELECTIVELY INHIBITS NOCICEPTION IN DSS-INDUCED COLITIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 151-152
Author(s):  
Y Yu ◽  
N N Jiménez-Vargas ◽  
Q K Tsang ◽  
C Lopez Lopez ◽  
J Jaramillo Polanco ◽  
...  
Keyword(s):  
Side Effects ◽  
Opioid Analgesic ◽  
Afferent Nerve ◽  
Colonic Tissue ◽  
Opioid Agonist ◽  
Tissue Ph ◽  
Dss Colitis ◽  
Nerve Recordings

Abstract Background Opioid drugs are used to treat pain in inflammatory bowel disease (IBD) but their side effects can cause serious morbidity. Therefore, we tested a novel opioid analgesic, ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) which selectively activates peripheral µ-opioid receptors at acidic pH, as occurs in inflamed tissue. Aims Evaluate whether NFEPP causes analgesia in the inflamed colon of DSS-colitis mice using both in vitro and in vivo techniques. Methods To measure the visceral motor reflex (VMR) in response to colorectal distention, EMG electrodes connected to a telemetric transmitter were implanted in mice (c57BL/6), after 10 days recovery acute dextran sodium sulfate (DSS) colitis was induced (5 days 2.5% DSS, 2 days water). VMR was measured 30 min after s.c. injection of vehicle or 0.2 mg/kg of NFEPP or fentanyl. Motility was assessed by fecal pellet count 1 hour after NFEPP. Colonic tissue pH was evaluated using the SNARF-4F-5 carboxylic acid probe. Excitability of mouse dorsal root ganglia (DRG) neurons was measured by recording the rheobase (minimum input current to fire an action potential) after superfusion of NFEPP (300 nM, 10 min) or vehicle at pH 6.5 or 7.4. Colonic afferent nerve responses to probing with a von Frey filament (1 gm) were examined before and after exposure to NFEPP (300 nM, 5 min superfusion) at pH 6.5 and 7.4 respectively. The data was analyzed with Welch’s t-test, 1- or 2-way ANOVA with post hoc Dunnett or Bonferroni or Tukey’s test. Results NFEPP significantly inhibited the VMR in response to distension in mice with colitis compared to vehicle (decreased response by 65%, P&lt;0.001). NFEPP had no effect in control mice. Conversely, fentanyl caused a similar decreased response in both groups (DSS 79% and control 67%, P&lt;0.001). Pelleting was not affected by NFEPP injection in either group compared to vehicle. The pH measurement revealed a more acidic environment in DSS colonic tissue (ΔpH0.37±0.14, P&lt;0.05) compared to controls. In patch-clamp studies, NFEPP decreased DRG excitability at pH 6.5 compared to the baseline and vehicle (increased rheobase 53.84%, P&lt;0.01 and 36.36%, P&lt;0.05 respectively) but had no effect at pH 7.4. In colonic afferent nerve recordings, NFEPP significantly attenuated afferent responses (28.9% P&lt;0.01) to probing at pH 6.5 but also had no effect at pH 7.4. Conclusions This pH-selective opioid agonist significantly inhibits pain at the site of inflammation where the tissue pH is acidic but has no effect in tissues where the pH is in the physiological range. Thus, NFEPP could be an effective opioid analgesic in IBD while being devoid of any unwanted side effects. Funding Agencies CCC

scholarly journals Exploring the Aversive and Anxiogenic Effects of Novel Kappa Opioid Receptor Agonists in Rats

2021 ◽  
Author(s):  
◽  
Aimee Culverhouse
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Prime Model ◽  
The Novel ◽  
Negative Consequences ◽  
Sprague Dawley ◽  
Initial Attempt ◽  
Kappa Opioid ◽  
Duration Of Action

<p>Drug addiction is characterised by uncontrolled, compulsive drug use despite negative consequences. As this disease has a high social and economic cost, greater attention is required in finding an effective treatment for individuals suffering addiction. Kappa opioid receptor (KOPr) agonists demonstrate anti-addiction effects in the rodent cocaine drug-prime model of reinstatement. Salvinorin A (Sal A), a novel non-nitrogenous KOPr agonist, has demonstrated reduced side-effects compared to traditional agonists. However, its short half-life and duration of action limit clinical development. The design of novel Sal A analogues with improved pharmacokinetics, anti-addiction effects, and reduced side-effects is an important step towards the pharmaceutical development of KOPr agonists. β-Tetrahydropyran Sal B (β-THP Sal B), Mesyl Sal B, ethoxymethyl salvinorin B ether (EOM Sal B), and Ethynyl Sal A (Ethy Sal A) have demonstrated anti-addiction effects by reducing cocaine-seeking behaviour in rats, but their aversive and anxiogenic properties have yet to be examined. Here the conditioned place aversion (CPA) paradigm is used to evaluate aversion and the elevated plus maze (EPM), light/dark test, and open field are utilised to measure anxiety in male Sprague-Dawley rats.  EOM Sal B (0.1 mg/kg, i.p) and Ethy Sal A (0.3 mg/kg, i.p) did not produce aversive effects, whereas the traditional KOPr agonist U50,488 (10 mg/kg, i.p), Sal A (0.3 mg/kg, i.p), and the novel analogue β-THP Sal B (1 mg/kg, i.p) produced significant aversion using the CPA protocol.  In the EPM all the novel analogues, β-THP Sal B, EOM Sal B, Mesyl Sal B, and Ethy Sal, A did not show a reduction in time spent on the open arm. In addition, EOM Sal B showed a significant increase in time spent on the open arm compared with Sal A (0.3 mg/kg, i.p). Sal A (0.3 and 1 mg/kg, i.p) showed significant anxiogenic effects, but the traditional agonist U50,488 did not. In the light/dark test Sal A (1 mg/kg, i.p) showed significant dose dependent anxiogenic effects with significant effects observed at 1 but not 0.3 mg/kg dose. This is in contrast to results observed in the EPM. The novel analogues EOM Sal B and β-THP Sal B demonstrated a non-significant trend toward anxiogenic behaviour in the light/dark test, but U50,488, Mesyl Sal B, and Ethy Sal A did not show significant reductions in time spent in the light box.  KOPr stimulation activates its associated G-proteins, allowing them to interact with several intracellular effectors. Activation of cAMP response element binding protein (CREB) can occur downstream of the KOPr signalling cascade. The phosphorylation of CREB is associated with dysphoria and stress-induced reinstatement of drug-seeking behaviour. An initial attempt to validate CREB assays was made.  The lack of behavioural anxiogenic and aversive side-effects with EOM Sal B, Mesyl Sal B and Ethy Sal A treatment demonstrates that the development of KOPr agonists with desirable effects and reduced side-effects is possible. These novel Sal A agonists provide promising candidates for pharmacotherapy development.</p>

scholarly journals Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Wang ◽  
Xiaoli Gou ◽  
Xiaojuan Yu ◽  
Dongdong Bai ◽  
Bowei Tan ◽  
...  
Keyword(s):  
Animal Models ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Hot Plate Test ◽  
Opioid Receptor Agonist ◽  
Antinociceptive Effects ◽  
Plasma Concentration Ratio ◽  
Cns Effects

Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.

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