Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

Paton, Kelly F.; Atigari, Diana Vivian; Kaska, Sophia; Prisinzano, Thomas E.; Kivell, Bronwyn M.

doi:10.1124/jpet.120.000134

Cited by 45 publications

(64 citation statements)

References 224 publications

(182 reference statements)

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“…Oxa-noribogaine, although a potent KOR agonist, does not show the acute pro-depressive or aversive effects, and induces desirable longterm effects in OUD models. It is not clear what mechanistically imparts these atypical features, whether differential KOR signaling [47][48][49][50] and or polypharmacology, 51,52 but, as a working hypothesis we propose an interplay between the KOR and the inherited iboga pharmacological activity. This constellation of primary molecular targets likely triggers neurotrophic and neuro-repair signaling pathways in several circuits (e.g.…”

Section: Discussionmentioning

confidence: 88%

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

Havel

Kruegel

Bechand

et al. 2021

Preprint

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Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities. Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states, highlighting an urgent need for radically different therapeutic approaches. Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt maladaptive habits including opioid use in drug-dependent humans. However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias. We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in addiction models and no cardiac pro-arrhythmic potential, compared to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine intake after a single dose in rat models of addiction and persistent reduction of morphine intake after a short treatment regimen. Oxa-noribogaine maintains and enhances the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga's cardiac liability. As such, oxa-iboga compounds represent candidates for a new kind of anti-addiction pharmacotherapeutics.

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Section: Discussionmentioning

confidence: 88%

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

Havel

Kruegel

Bechand

et al. 2021

Preprint

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“…Progress has been constrained by the lack of peripherally restricted KOR compounds, as well as short-acting antagonists. However, more recently, there has been a focused effort to develop both short-acting reversible antagonists (Page et al, 2019) and peripherally restricted agonists (Barber et al, 1994;Beck et al, 2019;Olesen et al, 2013;Paton et al, 2020;Shaw et al, 1989;Suzuki et al, 2017; Alleyne et al, in revision) to understand the role of KOR in pain-and itch-related behaviors.…”

Section: Discussionmentioning

confidence: 99%

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Madasu

Thang

Chilukuri

et al. 2020

Preprint

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Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3°C. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality.

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“…Furthermore, it does not induce anxiogenic or aversive effects as measured by elevated plus maze, forced swim test, and conditioned place aversion in rats (Atigari et al, 2019). Ultimately, these μ receptor/ κ receptor mixed agonists appear to show the same pre-clinical behavioural profile as what biased agonism is trying to achieve (Paton et al, 2020a. This can also be seen throughout this thesis with the significant improvements that kurkinorin has shown in terms of its side effect profile, which may be induced by latent selectivity for the κ receptor.…”

Section: Alternative Paths To Non-addictive Analgesicsmentioning

confidence: 96%

“…Indicating that the subcellular pathways are differentially regulated upon the formation of the heterodimer, possibly altering the signalling and bias of mixed agonists, including kurkinorin. Due to the lack of current research in the field and the potential benefit that mixed μ receptor/κ receptor may provide clinically, this is an area of opioid signalling that warrants further investigation (Paton et al, 2020a). To speed up the investigation into the effects if μ receptor/ κ receptor heterodimers have on cell signalling we can draw from the work into the effects if the δ receptor/μ receptor heterodimer.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

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Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

Alder¹

2021

Preprint

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Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. <div> </div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain.

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Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

Cited by 45 publications

References 224 publications

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

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