Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys

Huskinson, Sally L.; Platt, Donna M.; Brasfield, M; Follett, Meagan E.; Prisinzano, Thomas E.; Blough, Bruce E.; Freeman, Kevin B.

doi:10.1007/s00213-020-05519-7

Cited by 28 publications

(9 citation statements)

References 43 publications

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“…Studies with this probe also suggest that the G-protein pathway may mitigate motor coordination from analgesia, but dysphoria may also be dependent on the G-protein pathway. The results are comparable to a diphenylethylamine-based analogue HS666, another KOR biased agonist, which shows CPA in addition to analgesia and attenuated locomotor behavior, and in contrast to triazole 1.1 , and HS665, which show a more complete dissociation of KOR-induced dysphoria and sedation in mice models arguing for more KOR-biased ligands to be synthesized and investigated.…”

Section: Salvinorin Amentioning

confidence: 52%

Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide

Chakraborty

Majumdar

2020

Biochemistry

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Pain remains a very pervasive problem throughout medicine. Classical pain management is achieved through the use of opiates belonging to the mu opioid receptor (MOR) class, which have significant side effects that hinder their utility. Pharmacologists have been trying to develop opioids devoid of side effects since the isolation of morphine from papaver somniferum, more commonly known as opium by Sertürner in 1804. The natural products salvinorin A, mitragynine, and collybolide represent three nonmorphinan natural product-based targets, which are potent selective agonists of opioid receptors, and emerging next-generation analgesics. In this work, we review the phytochemistry and medicinal chemistry efforts on these templates and their effects on affinity, selectivity, analgesic actions, and a myriad of other opioid-receptor-related behavioral effects.

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Section: Salvinorin Amentioning

confidence: 52%

Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide

Chakraborty

Majumdar

2020

Biochemistry

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“…In addition, triazole 1.1 did not induce decreases in dopamine levels in comparison to U50,488 which decreased dopamine levels within the nucleus accumbens in a dose-dependent manner ( Brust et al, 2016 ). In rhesus monkeys, triazole 1.1 (0.01–0.32 mg/kg) did not induce sedative or motor impairment effects ( Huskinson et al, 2020 ). Furthermore, in rats, triazole 1.1 reduced oxycodone self-administration, and co-administration of oxycodone and triazole 1.1 enhanced anti-nociceptive effects ( Zamarripa et al, 2021 ).…”

Section: Diseases For Which the Kappa-opioid Receptors Has Therapeuti...mentioning

confidence: 99%

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

et al. 2022

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Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer’s disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein–biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.

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“…The antipruritic effects of triazole 1.1 were also blocked by a 24h pretreatment with NorBNI, which confirmed that the effect was KOR-specific. However, a very recent study on the effects of typical and atypical KOR agonists underlined that triazole 1.1 had no effect on its own, albeit reducing overall levels of scratching during time course determination [ 70 ]. In addition, an analysis of the locomotor activity showed that treatment with Triazole 1.1 did not affect locomotion at any of the doses tested, which was in contrast to what was observed with U50,488H.…”

Section: Kor Biased Agonismmentioning

confidence: 99%

Biased Opioid Ligands

2020

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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys

Cited by 28 publications

References 43 publications

Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide

Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

Biased Opioid Ligands

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