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

Chakraborty, Soumen; Majumdar, Susruta

doi:10.1021/acs.biochem.0c00629

Cited by 46 publications

(56 citation statements)

References 170 publications

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“…It is important to note, however, that TRV130 displays weak G-protein bias in vitro ( Schmid et al, 2017 ) and mixed safety results in rodent models ( Austin Zamarripa et al, 2018 ; Altarifi et al, 2017 ). Other MOR ligands with greater bias, such as SR17018 ( Schmid et al, 2017 ), show diminished respiratory depression in rodents compared to fentanyl ( Gillis et al, 2020a ), while PZM21 ( Manglik et al, 2016 ; Kudla et al, 2019 ) and mitragynine(s) ( Váradi et al, 2016 ; Kruegel et al, 2016 ; Kruegel et al, 2019 ; Chakraborty and Majumdar, 2020 ) display reduced abuse liability ( Yue et al, 2018 ; Hemby et al, 2019 ). Similarly, some KOR-selective G protein biased ligands such as HS666 ( Spetea et al, 2017 ), 6′GNTI ( Rives et al, 2012 ), and triazole 1.1 ( Brust et al, 2016 ) show a promising separation of place aversion from analgesia, unlike balanced KOR agonists.…”

Section: Introductionmentioning

confidence: 99%

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Uprety

Che

Zaidi

et al. 2021

eLife

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Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

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Section: Introductionmentioning

confidence: 99%

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Uprety

Che

Zaidi

et al. 2021

eLife

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“…We have previously demonstrated that systemic injections of the kratom extract and kratom alkaloids (7-hydroxymitragynine, paynantheine, speciogynine, and mitragynine) decrease voluntary alcohol drinking in mouse models of moderate and binge alcohol consumption, with the kratom alkaloid 7-hydroxymitragynine being the most efficacious ( Gutridge et al, 2020 ). Kratom alkaloids differ from opium-derived opioids and clinically used synthetic opioids in that upon binding to opioid receptors they activate the Gα i/o protein, without promoting β-arrestin recruitment to the receptor ( Kruegel et al, 2016 ; Váradi et al, 2016 ; Faouzi et al, 2020 ; Chakraborty and Majumdar, 2021 ). Several preclinical studies in mice strongly suggest that β-arrestin recruitment at the delta opioid receptor (δOR) is a liability for enhanced alcohol use and should be avoided ( Chiang et al, 2016 ; Robins et al, 2018 ; Gutridge et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

et al. 2021

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Background and Purpose:Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder.Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice.Key Results: Paynantheine (10 mg∙kg−1, i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg−1 doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg−1 (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures.Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.

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“…The major active alkaloid found in kratom is mitragynine, along with more than 40 other minor alkaloids. [11][12][13][14][15][16] In recent years, we have become interested in the chemistry and pharmacology of kratom alkaloids as probes to understand opioid receptor function. 11,[17][18][19][20][21][22][23] Previous reports from our group reported that mitragynine (possessing an indole core), its oxidation product 7OH (possessing an indolenine core), and mitragynine pseudoindoxyl (MP, a skeletal rearrangement product of 7OH with a spiro-pseudoindoxyl core) (Figure 1A), are all opioid antinociceptive agents 18,19 and Gprotein biased MOR agonists.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15][16] In recent years, we have become interested in the chemistry and pharmacology of kratom alkaloids as probes to understand opioid receptor function. 11,[17][18][19][20][21][22][23] Previous reports from our group reported that mitragynine (possessing an indole core), its oxidation product 7OH (possessing an indolenine core), and mitragynine pseudoindoxyl (MP, a skeletal rearrangement product of 7OH with a spiro-pseudoindoxyl core) (Figure 1A), are all opioid antinociceptive agents 18,19 and Gprotein biased MOR agonists. 17,18,20,22 We also reported oxidative metabolism of mitragynine to 7OH mitragynine using a CYP3A-mediated pathway following oral administration of mitragynine in mice.…”

Section: Introductionmentioning

confidence: 99%

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

Chakraborty

DiBerto

Faouzi

et al. 2021

Preprint

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Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom and its natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal beta-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and beta-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3-furanyl (SC13), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both β-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.

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

Cited by 46 publications

References 170 publications

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

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