The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys

Huskinson, Sally L.; Platt, Donna M.; Zamarripa, C. Austin; Dunaway, Kristen; Brasfield, M; Prisinzano, Thomas E.; Blough, Bruce E.; Freeman, Kevin B.

doi:10.1016/j.pbb.2022.173394

Cited by 12 publications

(2 citation statements)

References 32 publications

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“…208 Triazole 1.1 also had a reduced side-effect profile, both alone and in combination with oxycodone, in male rhesus monkeys. 208 While the analgesic effects and the lack of side effects of triazole 1.1 have been widely believed due to its G protein-biased agonistic activity on CNS KOR, in a recent letter, Beck et al used the "Brain Or IntestinaL EstimateD" permeation method (BOILED-Egg), a highly accurate predictive model that works by computing the lipophilicity and polarity of small molecules to estimate biological barrier penetration, and found that triazole 1.1 had a limited capacity to cross the BBB. 209 Thus, these authors argued that the analgesic activity of triazole 1.1 may be predominantly peripherally mediated.…”

Section: Iv3 Triazole 11mentioning

confidence: 92%

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

Khan

Sawyer

Akins

et al. 2022

European Journal of Medicinal Chemistry

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Section: Iv3 Triazole 11mentioning

confidence: 92%

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

Khan

Sawyer

Akins

et al. 2022

European Journal of Medicinal Chemistry

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“… Zamarripa et al (2021) showed that in male rats triazole 1.1 reduced oxycodone self-administration and increased antinociceptive effect of oxycodone in a hot plate test. Huskinson et al (2022) observed that in the rhesus monkey, triazole 1.1, nalfurafine and U50,488H all reduced oxycodone-induced scratching. However, U50,488H and nalfurafine, but not triazole 1.1, produced sedative-like and motor-impairing effects.…”

Section: Novel G Protein-biased Kappa Opioid Receptor Agonistsmentioning

confidence: 93%

Signaling underlying kappa opioid receptor-mediated behaviors in rodents

Liu‐Chen

Huang²

2022

Front. Neurosci.

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Kappa opioid receptor (KOR) agonists are potentially useful as analgesic and anti-pruritic agents, for prevention and treatment of substance use disorders, and for treatment of demyelinating diseases. However, side effects of KOR agonists, including psychotomimesis, dysphoria, and sedation, have caused early termination of clinical trials. Understanding the signaling mechanisms underlying the beneficial therapeutic effects and the adverse side effects may help in the development of KOR agonist compounds. In this review, we summarize the current knowledge in this regard in five sections. First, studies conducted on mutant mouse lines (GRK3-/-, p38alpha MAPK-/-, β-arrestin2-/-, phosphorylation-deficient KOR) are summarized. In addition, the abilities of four distinct KOR agonists, which have analgesic and anti-pruritic effects with different side effect profiles, to cause KOR phosphorylation are discussed. Second, investigations on the KOR agonist nalfurafine, both in vitro and in vivo are reviewed. Nalfurafine was the first KOR full agonist approved for clinical use and in the therapeutic dose range it did not produce significant side effects associated with typical KOR agonists. Third, large-scale high-throughput phosphoproteomic studies without a priori hypotheses are described. These studies have revealed that KOR-mediated side effects are associated with many signaling pathways. Fourth, several novel G protein-biased KOR agonists that have been characterized for in vitro biochemical properties and agonist biases and in vivo behavior effects are described. Lastly, possible mechanisms underlying KOR-mediated CPA, hypolocomotion and motor incoordination are discussed. Overall, it is agreed upon that the analgesic and anti-pruritic effects of KOR agonists are mediated via G protein signaling. However, there is no consensus on the mechanisms underlying their side effects. GRK3, p38 MAPK, β-arrestin2, mTOR pathway, CB1 cannabinoid receptor and protein kinase C have been implicated in one side effect or another. For drug discovery, after initial in vitro characterization, in vivo pharmacological characterizations in various behavior tests are still the most crucial steps and dose separation between beneficial therapeutic effects and adverse side effects are the critical determinant for the compounds to be moved forward for clinical development.

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Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys

Zamarripa,

Huskinson,

Townsend

et al. 2023

Psychopharmacology

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The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys

Cited by 12 publications

References 32 publications

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse

Signaling underlying kappa opioid receptor-mediated behaviors in rodents

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys

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